Olfactory decline in patients with chronic rhinosinusitis (CRS) after endoscopic sinus surgery is linked to superior turbinate eosinophilia, according to recent research released as an abstract from the American Academy of Allergy, Asthma, and Immunology annual meeting. The AAAAI canceled the meeting and provided abstracts and access to presenters for press coverage.

© Siri Stafford/Thinkstock

“Superior turbinate eosinophilia is highly associated with the olfactory decline in CRS patients 3 months after endoscopic sinus surgery,” Dawei Wu, MD, of Beijing Anzhen Hospital, Capital Medical University in Beijing, China, said in an interview.

There has been some research in the literature pointing to the link between CRS-associated olfactory dysfunction and superior turbinate eosinophilia. In a 2017 study, Lavin et al. found eosinophil markers in the superior turbinate tissue were elevated in patients with CRS with nasal polyps. One of the gene expressions of the eosinophil marker Charcot Leyden crystal protein (CLC) was inversely associated with olfactory threshold, which led the researchers to believe there was a link between olfactory decline and superior turbinate eosinophilia in these patients (Laryngoscope. 2017 Oct;127[10]:2210-2218).

Olfactory decline associated with CRS is the most common reason for loss of smell in ear, nose, and throat clinics, Dr. Wu said, but predicting this olfactory decline after endoscopic sinus surgery can be clinically challenging.

“The distinct feature of this smell disorder is the fluctuation in olfactory dysfunction which is mainly due to the recurrence of inflammation within the olfactory cleft. Notably, the level of eosinophils within the olfactory cleft significantly and positively correlated with the degree of olfactory dysfunction in patients with CRS both pre- and postoperatively,” he said.

Dr. Wu and colleagues conducted a prospective study to determine whether there was a link in CRS patients between preoperative superior turbinate eosinophilia and olfactory dysfunction after endoscopic sinus surgery. “We aimed to explore potential predictors of postoperative olfactory decline,” Dr. Wu said.

Overall, the investigators enrolled 78 patients with CRS in the study, where they received an olfactory assessment prior to and 3 months after endoscopic sinus surgery. The investigators used Sniffin’ Sticks (Burghardt; Wedel, Germany), a 12-item psychophysical smell test that uses everyday odors to conduct the olfactory assessment. If patients had a decrease in their threshold-discrimination-identification (TDI) score after surgery, they were determined to have olfactory deterioration. Prior to surgery, investigators measured olfactory cleft opacification using CT, with the olfactory cleft endoscopy scale used after surgery. The investigators also sampled patients’ superior turbinates at the time of surgery.

The results showed 23 of 78 patients (29.49%) had olfactory decline at 3 months after endoscopic sinus surgery. Those patients with olfactory decline had significantly higher tissue, blood eosinophil levels, and TDI scores before surgery, compared with patients with CRS who did not have any loss of smell. Patients with olfactory decline also had olfactory cleft opacification and olfactory cleft endoscopy scale scores, compared with patients who had no loss of smell after surgery.

One factor that predicted olfactory decline in these patients was an absolute count of 23.5 eosinophils per high-power field in the superior turbinate, researchers said (area under the ROC curve, 0.901). “Continuous elimination of the eosinophilic inflammation within the olfactory cleft in CRS patients with olfactory dysfunction may prevent the olfactory fluctuation after endoscopic sinus surgery,” Dr. Wu said.

Dr. Wu reports no relevant conflicts of interest.

SOURCE: Wu D et al. AAAAI. Abstract L7.

Olfactory decline in patients with chronic rhinosinusitis (CRS) after endoscopic sinus surgery is linked to superior turbinate eosinophilia, according to recent research released as an abstract from the American Academy of Allergy, Asthma, and Immunology annual meeting. The AAAAI canceled the meeting and provided abstracts and access to presenters for press coverage.

© Siri Stafford/Thinkstock

“Superior turbinate eosinophilia is highly associated with the olfactory decline in CRS patients 3 months after endoscopic sinus surgery,” Dawei Wu, MD, of Beijing Anzhen Hospital, Capital Medical University in Beijing, China, said in an interview.

There has been some research in the literature pointing to the link between CRS-associated olfactory dysfunction and superior turbinate eosinophilia. In a 2017 study, Lavin et al. found eosinophil markers in the superior turbinate tissue were elevated in patients with CRS with nasal polyps. One of the gene expressions of the eosinophil marker Charcot Leyden crystal protein (CLC) was inversely associated with olfactory threshold, which led the researchers to believe there was a link between olfactory decline and superior turbinate eosinophilia in these patients (Laryngoscope. 2017 Oct;127[10]:2210-2218).

Olfactory decline associated with CRS is the most common reason for loss of smell in ear, nose, and throat clinics, Dr. Wu said, but predicting this olfactory decline after endoscopic sinus surgery can be clinically challenging.

“The distinct feature of this smell disorder is the fluctuation in olfactory dysfunction which is mainly due to the recurrence of inflammation within the olfactory cleft. Notably, the level of eosinophils within the olfactory cleft significantly and positively correlated with the degree of olfactory dysfunction in patients with CRS both pre- and postoperatively,” he said.

Dr. Wu and colleagues conducted a prospective study to determine whether there was a link in CRS patients between preoperative superior turbinate eosinophilia and olfactory dysfunction after endoscopic sinus surgery. “We aimed to explore potential predictors of postoperative olfactory decline,” Dr. Wu said.

Overall, the investigators enrolled 78 patients with CRS in the study, where they received an olfactory assessment prior to and 3 months after endoscopic sinus surgery. The investigators used Sniffin’ Sticks (Burghardt; Wedel, Germany), a 12-item psychophysical smell test that uses everyday odors to conduct the olfactory assessment. If patients had a decrease in their threshold-discrimination-identification (TDI) score after surgery, they were determined to have olfactory deterioration. Prior to surgery, investigators measured olfactory cleft opacification using CT, with the olfactory cleft endoscopy scale used after surgery. The investigators also sampled patients’ superior turbinates at the time of surgery.

The results showed 23 of 78 patients (29.49%) had olfactory decline at 3 months after endoscopic sinus surgery. Those patients with olfactory decline had significantly higher tissue, blood eosinophil levels, and TDI scores before surgery, compared with patients with CRS who did not have any loss of smell. Patients with olfactory decline also had olfactory cleft opacification and olfactory cleft endoscopy scale scores, compared with patients who had no loss of smell after surgery.

One factor that predicted olfactory decline in these patients was an absolute count of 23.5 eosinophils per high-power field in the superior turbinate, researchers said (area under the ROC curve, 0.901). “Continuous elimination of the eosinophilic inflammation within the olfactory cleft in CRS patients with olfactory dysfunction may prevent the olfactory fluctuation after endoscopic sinus surgery,” Dr. Wu said.

Dr. Wu reports no relevant conflicts of interest.

SOURCE: Wu D et al. AAAAI. Abstract L7.

Olfactory decline in patients with chronic rhinosinusitis (CRS) after endoscopic sinus surgery is linked to superior turbinate eosinophilia, according to recent research released as an abstract from the American Academy of Allergy, Asthma, and Immunology annual meeting. The AAAAI canceled the meeting and provided abstracts and access to presenters for press coverage.

© Siri Stafford/Thinkstock

“Superior turbinate eosinophilia is highly associated with the olfactory decline in CRS patients 3 months after endoscopic sinus surgery,” Dawei Wu, MD, of Beijing Anzhen Hospital, Capital Medical University in Beijing, China, said in an interview.

There has been some research in the literature pointing to the link between CRS-associated olfactory dysfunction and superior turbinate eosinophilia. In a 2017 study, Lavin et al. found eosinophil markers in the superior turbinate tissue were elevated in patients with CRS with nasal polyps. One of the gene expressions of the eosinophil marker Charcot Leyden crystal protein (CLC) was inversely associated with olfactory threshold, which led the researchers to believe there was a link between olfactory decline and superior turbinate eosinophilia in these patients (Laryngoscope. 2017 Oct;127[10]:2210-2218).

Olfactory decline associated with CRS is the most common reason for loss of smell in ear, nose, and throat clinics, Dr. Wu said, but predicting this olfactory decline after endoscopic sinus surgery can be clinically challenging.

“The distinct feature of this smell disorder is the fluctuation in olfactory dysfunction which is mainly due to the recurrence of inflammation within the olfactory cleft. Notably, the level of eosinophils within the olfactory cleft significantly and positively correlated with the degree of olfactory dysfunction in patients with CRS both pre- and postoperatively,” he said.

Dr. Wu and colleagues conducted a prospective study to determine whether there was a link in CRS patients between preoperative superior turbinate eosinophilia and olfactory dysfunction after endoscopic sinus surgery. “We aimed to explore potential predictors of postoperative olfactory decline,” Dr. Wu said.

Overall, the investigators enrolled 78 patients with CRS in the study, where they received an olfactory assessment prior to and 3 months after endoscopic sinus surgery. The investigators used Sniffin’ Sticks (Burghardt; Wedel, Germany), a 12-item psychophysical smell test that uses everyday odors to conduct the olfactory assessment. If patients had a decrease in their threshold-discrimination-identification (TDI) score after surgery, they were determined to have olfactory deterioration. Prior to surgery, investigators measured olfactory cleft opacification using CT, with the olfactory cleft endoscopy scale used after surgery. The investigators also sampled patients’ superior turbinates at the time of surgery.

The results showed 23 of 78 patients (29.49%) had olfactory decline at 3 months after endoscopic sinus surgery. Those patients with olfactory decline had significantly higher tissue, blood eosinophil levels, and TDI scores before surgery, compared with patients with CRS who did not have any loss of smell. Patients with olfactory decline also had olfactory cleft opacification and olfactory cleft endoscopy scale scores, compared with patients who had no loss of smell after surgery.

One factor that predicted olfactory decline in these patients was an absolute count of 23.5 eosinophils per high-power field in the superior turbinate, researchers said (area under the ROC curve, 0.901). “Continuous elimination of the eosinophilic inflammation within the olfactory cleft in CRS patients with olfactory dysfunction may prevent the olfactory fluctuation after endoscopic sinus surgery,” Dr. Wu said.

Dr. Wu reports no relevant conflicts of interest.

SOURCE: Wu D et al. AAAAI. Abstract L7.

Early results from the massive National Cardiovascular Data Registry Left Atrial Appendage Occlusion Registry indicate that the rollout of the Watchman device into routine clinical practice is going smoothly, with a higher implant success rate and a substantially lower in-hospital complication rate than that seen in the pivotal randomized clinical trials, James V. Freeman, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

American College of Cardiology

These real-world results are particularly impressive because the 38,158 registry participants were on average significantly older and sicker than were patients in the clinical trials. They were at higher risk of both stroke and bleeding, yet they fared better in terms of procedural safety, observed Dr. Freeman, an electrophysiologist and director of the Yale University Atrial Fibrillation Center in New Haven, Conn.

“You always worry that once you get outside of the clinical trials setting and you roll out to a large number of centers, including some that are relatively low volume, that you’re going to start to see higher rates of complications. And overall, broadly speaking, the rates of adverse events were quite reassuring,” he said.

The registry, maintained by the ACC, serves as the postmarketing surveillance tool mandated by the Food and Drug Administration and Centers for Medicare & Medicaid Services. The 38,158 participants make this registry the world’s largest patient experience with the Watchman device by many orders of magnitude. Dr. Freeman’s report included patients enrolled during 2016-2018 who were treated at 495 hospitals by 1,318 physician interventionalists. CMS reimbursement requires participation in the registry, which captures more than 95% of all Watchman procedures done in the United States. Although Dr. Freeman presented only the acute in-hospital outcomes, active follow-up for adverse events and medical therapy will be conducted at 45 days, 6 months, and 1 and 2 years.

Participants in the Left Atrial Appendage Occlusion (LAAO) Registry averaged 76.1 years of age, which is 2-4 years older than patients in the pivotal PROTECT-AF and PREVAIL trials or the 1,025-patient EWOLUTION registry. The LAAO Registry participants had a mean CHA2DS2-VASc score of 4.6, compared with 3.4 in PROTECT-AF and 3.8 in PREVAIL. Their mean HAS BLED score was 3.0. Thirty percent had a prior ischemic stroke or transient ischemic attack, 12% had a prior intracranial hemorrhage, and 69% had a history of clinically relevant bleeding. Thirty percent had heart failure, 92% were hypertensive, and 30% had diabetes.

“The take home here is that these patients were at moderate to high risk of stroke and they also carried a high risk of bleeding and therefore had some relative contraindication to anticoagulation,” according to the cardiologist. “The patient population overall is really in accordance with the CMS guidance. We’re not seeing a lot of patients who are getting this device for a lifestyle indication. Most of these patients are really stuck between a rock and a hard place.”

Most hospitals offering the Watchman did 10-40 cases per year. The median annual physician volume was 12 cases. However, there was substantial variation in both hospital and physician volumes.

The device was deployed in 93% of procedures attempted; roughly half of cancellations were cause by LAAO thrombus detected on the day of the procedure. The acute procedural success rate when the device was deployed was 98.3%, compared with 90.9% in PROTECT-AF and 95.1% in PREVAIL. The rate of device margin residual leak of 5 mm or more among registry participants with an acutely successful procedure was 0.2%.

The rate of any major in-hospital complication in the LAAO Registry was 2.16%, the most common of which was pericardial effusion requiring intervention, which occurred in 1.39% of cases. The major bleeding rate was 1.25%. The stroke/transient ischemic attack rate was 0.17%. Systemic arterial embolism was a rare event, occurring in less than 0.01% of patients, as was acute MI, with an incidence of 0.04%. Device embolization occurred in 0.07% of patients.

By comparison, the 7-day rate of pericardial effusion requiring intervention was 4.0% in PROTECT-AF and 1.9% in PREVAIL, with procedure-related stroke rates of 1.1% and 0.7%, respectively, and device embolization rates of 0.4% and 0.7%. The major bleeding rate in PROTECT-AF was 3.5%, nearly triple that in the real-world registry.

Discussant Mark A. Estes, MD, characterized the acute outcomes in the LAAO Registry as “an improvement – a considerable improvement – over some of the early data in PREVAIL and PROTECT-AF.” He credited this to the “very robust validation procedure” the Watchman closure device has undergone, which included the clinical trials, regulatory requirements for training and patient selection, and mandatory reporting of outcomes in the registry.

He noted that a lot is happening now with the Watchman device. There are a couple of dozen prospective clinical trials, including one on the Watchman versus direct oral anticoagulant (DOAC) therapy and another on left atrial ablation plus left atrial appendage closure versus a DOAC. A new-generation Watchman device, the Watchman FLX, is approved in Europe and undergoing an ongoing FDA-mandated approval trial in the United States.

“It has a lot of technical advantages,” according to Dr. Estes, an electrophysiologist and professor of medicine at the University of Pittsburgh.

Current guidelines give LAAO a class IIb rating, meaning it “could be considered” in patients with atrial fibrillation at increased risk of stroke who have a contraindication to long-term anticoagulation. Dr. Estes asked: Does the LAAO Registry data warrant a rating upgrade to a stronger recommendation?

Dr. Freeman replied that the new data should allay the guideline writers’ and government regulators’ concerns regarding acute procedural safety. But that’s only part of the picture. He and his coinvestigators are busy gathering data on intermediate-term outcomes, analyzing the impact of various strategies for periprocedural and long-term management of antiplatelet and anticoagulant medications with an eye toward identifying best practices, and investigating the relationship between procedural volume and outcomes, information, which could have an impact on the next iteration of the guidelines.

Simultaneous with his presentation at ACC 2020, the study was published online (J Am Coll Cardiol. 2020 Mar 13;75[13]1503-18).

In an accompanying editorial, Dhanunjaya Lakkireddy, MD, commented that an important contribution of the LAAO Registry is its inclusion of an enormous number of patients with contraindications to oral anticoagulation, a population excluded from the PROTECT-AF and PREVAIL randomized trials.

The short-term results of the registry suggest a relaxation of the current strict requirement for surgical backup during Watchman procedures is in order, added Dr. Lakkireddy, professor of medicine at the University of Missouri, Columbia, and medical director of the Kansas City Heart Rhythm Institute (J Am Coll Cardiol. 2020 Mar 13;75[13]:1519-22).

Dr. Freeman reported serving as a consultant to Boston Scientific, which markets the Watchman, as well as to Medtronic, Janssen, and Biosense Webster.

bjancin@mdedge.com

SOURCE: Freeman JF. ACC 2020, Abstract 409-10.

Early results from the massive National Cardiovascular Data Registry Left Atrial Appendage Occlusion Registry indicate that the rollout of the Watchman device into routine clinical practice is going smoothly, with a higher implant success rate and a substantially lower in-hospital complication rate than that seen in the pivotal randomized clinical trials, James V. Freeman, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

American College of Cardiology

These real-world results are particularly impressive because the 38,158 registry participants were on average significantly older and sicker than were patients in the clinical trials. They were at higher risk of both stroke and bleeding, yet they fared better in terms of procedural safety, observed Dr. Freeman, an electrophysiologist and director of the Yale University Atrial Fibrillation Center in New Haven, Conn.

“You always worry that once you get outside of the clinical trials setting and you roll out to a large number of centers, including some that are relatively low volume, that you’re going to start to see higher rates of complications. And overall, broadly speaking, the rates of adverse events were quite reassuring,” he said.

The registry, maintained by the ACC, serves as the postmarketing surveillance tool mandated by the Food and Drug Administration and Centers for Medicare & Medicaid Services. The 38,158 participants make this registry the world’s largest patient experience with the Watchman device by many orders of magnitude. Dr. Freeman’s report included patients enrolled during 2016-2018 who were treated at 495 hospitals by 1,318 physician interventionalists. CMS reimbursement requires participation in the registry, which captures more than 95% of all Watchman procedures done in the United States. Although Dr. Freeman presented only the acute in-hospital outcomes, active follow-up for adverse events and medical therapy will be conducted at 45 days, 6 months, and 1 and 2 years.

Participants in the Left Atrial Appendage Occlusion (LAAO) Registry averaged 76.1 years of age, which is 2-4 years older than patients in the pivotal PROTECT-AF and PREVAIL trials or the 1,025-patient EWOLUTION registry. The LAAO Registry participants had a mean CHA2DS2-VASc score of 4.6, compared with 3.4 in PROTECT-AF and 3.8 in PREVAIL. Their mean HAS BLED score was 3.0. Thirty percent had a prior ischemic stroke or transient ischemic attack, 12% had a prior intracranial hemorrhage, and 69% had a history of clinically relevant bleeding. Thirty percent had heart failure, 92% were hypertensive, and 30% had diabetes.

“The take home here is that these patients were at moderate to high risk of stroke and they also carried a high risk of bleeding and therefore had some relative contraindication to anticoagulation,” according to the cardiologist. “The patient population overall is really in accordance with the CMS guidance. We’re not seeing a lot of patients who are getting this device for a lifestyle indication. Most of these patients are really stuck between a rock and a hard place.”

Most hospitals offering the Watchman did 10-40 cases per year. The median annual physician volume was 12 cases. However, there was substantial variation in both hospital and physician volumes.

The device was deployed in 93% of procedures attempted; roughly half of cancellations were cause by LAAO thrombus detected on the day of the procedure. The acute procedural success rate when the device was deployed was 98.3%, compared with 90.9% in PROTECT-AF and 95.1% in PREVAIL. The rate of device margin residual leak of 5 mm or more among registry participants with an acutely successful procedure was 0.2%.

The rate of any major in-hospital complication in the LAAO Registry was 2.16%, the most common of which was pericardial effusion requiring intervention, which occurred in 1.39% of cases. The major bleeding rate was 1.25%. The stroke/transient ischemic attack rate was 0.17%. Systemic arterial embolism was a rare event, occurring in less than 0.01% of patients, as was acute MI, with an incidence of 0.04%. Device embolization occurred in 0.07% of patients.

By comparison, the 7-day rate of pericardial effusion requiring intervention was 4.0% in PROTECT-AF and 1.9% in PREVAIL, with procedure-related stroke rates of 1.1% and 0.7%, respectively, and device embolization rates of 0.4% and 0.7%. The major bleeding rate in PROTECT-AF was 3.5%, nearly triple that in the real-world registry.

Discussant Mark A. Estes, MD, characterized the acute outcomes in the LAAO Registry as “an improvement – a considerable improvement – over some of the early data in PREVAIL and PROTECT-AF.” He credited this to the “very robust validation procedure” the Watchman closure device has undergone, which included the clinical trials, regulatory requirements for training and patient selection, and mandatory reporting of outcomes in the registry.

He noted that a lot is happening now with the Watchman device. There are a couple of dozen prospective clinical trials, including one on the Watchman versus direct oral anticoagulant (DOAC) therapy and another on left atrial ablation plus left atrial appendage closure versus a DOAC. A new-generation Watchman device, the Watchman FLX, is approved in Europe and undergoing an ongoing FDA-mandated approval trial in the United States.

“It has a lot of technical advantages,” according to Dr. Estes, an electrophysiologist and professor of medicine at the University of Pittsburgh.

Current guidelines give LAAO a class IIb rating, meaning it “could be considered” in patients with atrial fibrillation at increased risk of stroke who have a contraindication to long-term anticoagulation. Dr. Estes asked: Does the LAAO Registry data warrant a rating upgrade to a stronger recommendation?

Dr. Freeman replied that the new data should allay the guideline writers’ and government regulators’ concerns regarding acute procedural safety. But that’s only part of the picture. He and his coinvestigators are busy gathering data on intermediate-term outcomes, analyzing the impact of various strategies for periprocedural and long-term management of antiplatelet and anticoagulant medications with an eye toward identifying best practices, and investigating the relationship between procedural volume and outcomes, information, which could have an impact on the next iteration of the guidelines.

Simultaneous with his presentation at ACC 2020, the study was published online (J Am Coll Cardiol. 2020 Mar 13;75[13]1503-18).

In an accompanying editorial, Dhanunjaya Lakkireddy, MD, commented that an important contribution of the LAAO Registry is its inclusion of an enormous number of patients with contraindications to oral anticoagulation, a population excluded from the PROTECT-AF and PREVAIL randomized trials.

The short-term results of the registry suggest a relaxation of the current strict requirement for surgical backup during Watchman procedures is in order, added Dr. Lakkireddy, professor of medicine at the University of Missouri, Columbia, and medical director of the Kansas City Heart Rhythm Institute (J Am Coll Cardiol. 2020 Mar 13;75[13]:1519-22).

Dr. Freeman reported serving as a consultant to Boston Scientific, which markets the Watchman, as well as to Medtronic, Janssen, and Biosense Webster.

bjancin@mdedge.com

SOURCE: Freeman JF. ACC 2020, Abstract 409-10.

Early results from the massive National Cardiovascular Data Registry Left Atrial Appendage Occlusion Registry indicate that the rollout of the Watchman device into routine clinical practice is going smoothly, with a higher implant success rate and a substantially lower in-hospital complication rate than that seen in the pivotal randomized clinical trials, James V. Freeman, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

American College of Cardiology

These real-world results are particularly impressive because the 38,158 registry participants were on average significantly older and sicker than were patients in the clinical trials. They were at higher risk of both stroke and bleeding, yet they fared better in terms of procedural safety, observed Dr. Freeman, an electrophysiologist and director of the Yale University Atrial Fibrillation Center in New Haven, Conn.

“You always worry that once you get outside of the clinical trials setting and you roll out to a large number of centers, including some that are relatively low volume, that you’re going to start to see higher rates of complications. And overall, broadly speaking, the rates of adverse events were quite reassuring,” he said.

The registry, maintained by the ACC, serves as the postmarketing surveillance tool mandated by the Food and Drug Administration and Centers for Medicare & Medicaid Services. The 38,158 participants make this registry the world’s largest patient experience with the Watchman device by many orders of magnitude. Dr. Freeman’s report included patients enrolled during 2016-2018 who were treated at 495 hospitals by 1,318 physician interventionalists. CMS reimbursement requires participation in the registry, which captures more than 95% of all Watchman procedures done in the United States. Although Dr. Freeman presented only the acute in-hospital outcomes, active follow-up for adverse events and medical therapy will be conducted at 45 days, 6 months, and 1 and 2 years.

Participants in the Left Atrial Appendage Occlusion (LAAO) Registry averaged 76.1 years of age, which is 2-4 years older than patients in the pivotal PROTECT-AF and PREVAIL trials or the 1,025-patient EWOLUTION registry. The LAAO Registry participants had a mean CHA2DS2-VASc score of 4.6, compared with 3.4 in PROTECT-AF and 3.8 in PREVAIL. Their mean HAS BLED score was 3.0. Thirty percent had a prior ischemic stroke or transient ischemic attack, 12% had a prior intracranial hemorrhage, and 69% had a history of clinically relevant bleeding. Thirty percent had heart failure, 92% were hypertensive, and 30% had diabetes.

“The take home here is that these patients were at moderate to high risk of stroke and they also carried a high risk of bleeding and therefore had some relative contraindication to anticoagulation,” according to the cardiologist. “The patient population overall is really in accordance with the CMS guidance. We’re not seeing a lot of patients who are getting this device for a lifestyle indication. Most of these patients are really stuck between a rock and a hard place.”

Most hospitals offering the Watchman did 10-40 cases per year. The median annual physician volume was 12 cases. However, there was substantial variation in both hospital and physician volumes.

The device was deployed in 93% of procedures attempted; roughly half of cancellations were cause by LAAO thrombus detected on the day of the procedure. The acute procedural success rate when the device was deployed was 98.3%, compared with 90.9% in PROTECT-AF and 95.1% in PREVAIL. The rate of device margin residual leak of 5 mm or more among registry participants with an acutely successful procedure was 0.2%.

The rate of any major in-hospital complication in the LAAO Registry was 2.16%, the most common of which was pericardial effusion requiring intervention, which occurred in 1.39% of cases. The major bleeding rate was 1.25%. The stroke/transient ischemic attack rate was 0.17%. Systemic arterial embolism was a rare event, occurring in less than 0.01% of patients, as was acute MI, with an incidence of 0.04%. Device embolization occurred in 0.07% of patients.

By comparison, the 7-day rate of pericardial effusion requiring intervention was 4.0% in PROTECT-AF and 1.9% in PREVAIL, with procedure-related stroke rates of 1.1% and 0.7%, respectively, and device embolization rates of 0.4% and 0.7%. The major bleeding rate in PROTECT-AF was 3.5%, nearly triple that in the real-world registry.

Discussant Mark A. Estes, MD, characterized the acute outcomes in the LAAO Registry as “an improvement – a considerable improvement – over some of the early data in PREVAIL and PROTECT-AF.” He credited this to the “very robust validation procedure” the Watchman closure device has undergone, which included the clinical trials, regulatory requirements for training and patient selection, and mandatory reporting of outcomes in the registry.

He noted that a lot is happening now with the Watchman device. There are a couple of dozen prospective clinical trials, including one on the Watchman versus direct oral anticoagulant (DOAC) therapy and another on left atrial ablation plus left atrial appendage closure versus a DOAC. A new-generation Watchman device, the Watchman FLX, is approved in Europe and undergoing an ongoing FDA-mandated approval trial in the United States.

“It has a lot of technical advantages,” according to Dr. Estes, an electrophysiologist and professor of medicine at the University of Pittsburgh.

Current guidelines give LAAO a class IIb rating, meaning it “could be considered” in patients with atrial fibrillation at increased risk of stroke who have a contraindication to long-term anticoagulation. Dr. Estes asked: Does the LAAO Registry data warrant a rating upgrade to a stronger recommendation?

Dr. Freeman replied that the new data should allay the guideline writers’ and government regulators’ concerns regarding acute procedural safety. But that’s only part of the picture. He and his coinvestigators are busy gathering data on intermediate-term outcomes, analyzing the impact of various strategies for periprocedural and long-term management of antiplatelet and anticoagulant medications with an eye toward identifying best practices, and investigating the relationship between procedural volume and outcomes, information, which could have an impact on the next iteration of the guidelines.

Simultaneous with his presentation at ACC 2020, the study was published online (J Am Coll Cardiol. 2020 Mar 13;75[13]1503-18).

In an accompanying editorial, Dhanunjaya Lakkireddy, MD, commented that an important contribution of the LAAO Registry is its inclusion of an enormous number of patients with contraindications to oral anticoagulation, a population excluded from the PROTECT-AF and PREVAIL randomized trials.

The short-term results of the registry suggest a relaxation of the current strict requirement for surgical backup during Watchman procedures is in order, added Dr. Lakkireddy, professor of medicine at the University of Missouri, Columbia, and medical director of the Kansas City Heart Rhythm Institute (J Am Coll Cardiol. 2020 Mar 13;75[13]:1519-22).

Dr. Freeman reported serving as a consultant to Boston Scientific, which markets the Watchman, as well as to Medtronic, Janssen, and Biosense Webster.

bjancin@mdedge.com

SOURCE: Freeman JF. ACC 2020, Abstract 409-10.

June 9, 2020 — Editor’s note: The study on which this news story is based has been retracted by the journal. The retraction notice can be found here. 

Cotton and surgical masks were not effective at filtering SARS-CoV-2 during coughs from patients infected with the virus, according to Seongman Bae, MD, of the University of Ulsan College of Medicine in Seoul, South Korea, and associates.

The report was published in Annals of Internal Medicine.

Because the COVID-19 pandemic has caused a shortage of N95 and surgical masks, cotton masks have gained interest as a substitute, as surgical masks have been shown to effectively filter influenza virus, the researchers wrote. However, the size of and concentrations of SARS-CoV-2 in aerosols generated during coughing are unknown.

To compare the effectiveness of cotton and surgical masks, a group of patients infected with SARS-CoV-2 coughed into petri dishes while wearing no mask, a surgical mask, and a cotton mask. The mask surfaces were swabbed afterward to assess viral positivity on the mask itself.

The median nasopharyngeal and saliva viral load was 5.66 log copies/mL and 4.00 log copies/mL, respectively. The median viral loads after coughing was 2.56 log copies/mL without a mask, 2.42 log copies/mL with a surgical mask, and 1.85 log copies/mL with a cotton mask. All outer surfaces of the mask were positive for SARS-CoV-2, while most inner surfaces were negative.

The investigators acknowledged that the test did not include N95 masks and does not reflect the actual infection transmission, and that they didn’t know whether cotton or surgical masks shorten the travel distance of droplets while coughing.

“Further study is needed to recommend whether face masks decrease transmission of virus from asymptomatic individuals or those with suspected COVID-19 who are not coughing,” they added.

The study was funded by a grant from the government-wide R&D Fund Project for Infectious Disease Research. The investigators reported that they had no conflicts of interest.

lfranki@mdedge.com

SOURCE: Bae S et al. Ann Intern Med. 2020 Apr 6. doi: 10.7326/M20-1342.

Correction, 4/9/20: The headline of an earlier version of this article misstated a finding of this study. Whether cotton and surgical masks can block transmission was not investigated.

June 9, 2020 — Editor’s note: The study on which this news story is based has been retracted by the journal. The retraction notice can be found here. 

Cotton and surgical masks were not effective at filtering SARS-CoV-2 during coughs from patients infected with the virus, according to Seongman Bae, MD, of the University of Ulsan College of Medicine in Seoul, South Korea, and associates.

The report was published in Annals of Internal Medicine.

Because the COVID-19 pandemic has caused a shortage of N95 and surgical masks, cotton masks have gained interest as a substitute, as surgical masks have been shown to effectively filter influenza virus, the researchers wrote. However, the size of and concentrations of SARS-CoV-2 in aerosols generated during coughing are unknown.

To compare the effectiveness of cotton and surgical masks, a group of patients infected with SARS-CoV-2 coughed into petri dishes while wearing no mask, a surgical mask, and a cotton mask. The mask surfaces were swabbed afterward to assess viral positivity on the mask itself.

The median nasopharyngeal and saliva viral load was 5.66 log copies/mL and 4.00 log copies/mL, respectively. The median viral loads after coughing was 2.56 log copies/mL without a mask, 2.42 log copies/mL with a surgical mask, and 1.85 log copies/mL with a cotton mask. All outer surfaces of the mask were positive for SARS-CoV-2, while most inner surfaces were negative.

The investigators acknowledged that the test did not include N95 masks and does not reflect the actual infection transmission, and that they didn’t know whether cotton or surgical masks shorten the travel distance of droplets while coughing.

“Further study is needed to recommend whether face masks decrease transmission of virus from asymptomatic individuals or those with suspected COVID-19 who are not coughing,” they added.

The study was funded by a grant from the government-wide R&D Fund Project for Infectious Disease Research. The investigators reported that they had no conflicts of interest.

lfranki@mdedge.com

SOURCE: Bae S et al. Ann Intern Med. 2020 Apr 6. doi: 10.7326/M20-1342.

Correction, 4/9/20: The headline of an earlier version of this article misstated a finding of this study. Whether cotton and surgical masks can block transmission was not investigated.

June 9, 2020 — Editor’s note: The study on which this news story is based has been retracted by the journal. The retraction notice can be found here. 

Cotton and surgical masks were not effective at filtering SARS-CoV-2 during coughs from patients infected with the virus, according to Seongman Bae, MD, of the University of Ulsan College of Medicine in Seoul, South Korea, and associates.

The report was published in Annals of Internal Medicine.

Because the COVID-19 pandemic has caused a shortage of N95 and surgical masks, cotton masks have gained interest as a substitute, as surgical masks have been shown to effectively filter influenza virus, the researchers wrote. However, the size of and concentrations of SARS-CoV-2 in aerosols generated during coughing are unknown.

To compare the effectiveness of cotton and surgical masks, a group of patients infected with SARS-CoV-2 coughed into petri dishes while wearing no mask, a surgical mask, and a cotton mask. The mask surfaces were swabbed afterward to assess viral positivity on the mask itself.

The median nasopharyngeal and saliva viral load was 5.66 log copies/mL and 4.00 log copies/mL, respectively. The median viral loads after coughing was 2.56 log copies/mL without a mask, 2.42 log copies/mL with a surgical mask, and 1.85 log copies/mL with a cotton mask. All outer surfaces of the mask were positive for SARS-CoV-2, while most inner surfaces were negative.

The investigators acknowledged that the test did not include N95 masks and does not reflect the actual infection transmission, and that they didn’t know whether cotton or surgical masks shorten the travel distance of droplets while coughing.

“Further study is needed to recommend whether face masks decrease transmission of virus from asymptomatic individuals or those with suspected COVID-19 who are not coughing,” they added.

The study was funded by a grant from the government-wide R&D Fund Project for Infectious Disease Research. The investigators reported that they had no conflicts of interest.

lfranki@mdedge.com

SOURCE: Bae S et al. Ann Intern Med. 2020 Apr 6. doi: 10.7326/M20-1342.

Correction, 4/9/20: The headline of an earlier version of this article misstated a finding of this study. Whether cotton and surgical masks can block transmission was not investigated.

►Zachary Reese, MD, Chief Medical Resident, VABHS and Beth Israel Deaconess Medical Center (BIDMC):Dr. Weller, the differential diagnosis for altered mental status is quite broad. How does the presence of clonus change or focus your approach to altered mental status?

►Jason Weller, MD, Instructor of Neurology, Boston Medical Center (BMC) and VABHS:The presence of clonus does not significantly narrow the differential. It does, however, suggest a central component to the patient’s altered mental status. Specifically, it implies that the underlying process, whether systemic or neurologic, interferes with central nervous system (CNS) control of the neuromuscular system.¹ The differential is still quite broad and includes metabolic derangements (eg, uremia, electrolyte disturbances, hypercarbia, and thyroid dysfunction), medication toxicity from olanzapine or duloxetine, and vascular processes (eg, CNS vasculitis). Infectious etiologies, both within the CNS and systemically, can cause encephalopathy, as can autoimmune processes, such as immune-mediated encephalitis. Finally, primary neurologic conditions such as myoclonic epilepsy can be considered. Given the patient’s medical history, serotonin syndrome must be considered.

►Dr. Reese: Given the concern for serotonin syndrome, the admitting medical team discontinued the patient’s duloxetine. Dr. Weller, what is the pathophysiology of serotonin syndrome, and how is it diagnosed?

►Dr. Weller: Serotonin is ubiquitous throughout the body and brain. Serotonin syndrome is caused by excess endogenous or exogenous serotonin, and this is usually caused by a variety of medications. The symptoms range from tachycardia, agitation, and diaphoresis to sustained clonus, hyperthermia, and shock.^2,3 The extent of serotonin syndrome is typically thought to reflect the degree of serotonergic activity.⁴

Serotonin syndrome is a clinical diagnosis. While there are no tests that can confirm the diagnosis, the Hunter criteria can be used to assist with making the diagnosis.⁵ Per the Hunter criteria, a patient can be diagnosed with serotonin syndrome if they have taken a serotonergic agent and have at least 1 of the following: spontaneous clonus, inducible or ocular clonus with agitation or diaphoresis, tremor and hyperreflexia, or hypertonia with fever and clonus. This patient had taken duloxetine and had inducible clonus and diaphoresis, thus suggesting a diagnosis of serotonin syndrome.

►Dr. Reese: Aside from selective serotonin reuptake inhibitors (SSRIs), are there other medications that we typically prescribe that can cause serotonin syndrome?

►Dr. Weller: In addition to SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs), other commonly prescribed medications that can cause serotonin syndrome are 5-HT3 antagonists (eg, ondansetron), 5-HT agonists (eg, triptans), and opioids (eg, fentanyl and tramadol). There are also case reports of atypical antipsychotics (eg, olanzapine) causing serotonin syndrome because of their antagonism of the 5-HT2 and 5-HT3 receptors.² Additionally, linezolid is commonly overlooked as a cause of serotonin syndrome given its action as a monoamine oxidase inhibitor.⁴ In this patient, it would be prudent to discontinue olanzapine and duloxetine.

►Dr. Reese: Duloxetine, olanzapine, and buprenorphine/naloxone were discontinuedgiven concern for serotonin syndrome. Although there are not strong data that buprenorphine/ naloxone can cause serotonin syndrome, the team discontinued the medication in case it might be contributing to the patient’s encephalopathy, while closely monitoring the patient for withdrawal. There was a rapid improvement in the patient’s symptoms over the 24 hours after discontinuation of the 3 medications.

As part of the initial workup, the patient received a computed tomography (CT) scan of his chest to follow up pulmonary nodules identified 16 months prior. The CT scan showed interval growth of the pulmonary nodules in the right lower lobe to 2 cm with extension into the major fissure, which was concerning for malignancy. Plans were made for an outpatient positron emission tomography (PET) scan after hospital discharge.

Dr. Schlechter and Dr. Rangachari, what factors can help us determine whether or not further workup of a malignancy should occur before discharge or can be deferred to the outpatient setting?

►Benjamin Schlechter, MD, Instructor in Medicine, BIDMC; and Deepa Rangachari, MD, Assistant Professor of Medicine, BIDMC: Key considerations in this domain include rapidity of growth and any threat to critical end-organ function (ie, brain, heart, lungs, kidney, and liver). If the malignancy is bulky and/or rapidly progressing to the point that the patient has significant symptoms burden and/or end-organ dysfunction, then initiating the evaluation as an inpatient may be necessary. For suspected intrathoracic malignancies, considering whether this may be a high-grade process (ie, small cell lung cancer) is often a vital branch point. Key considerations in this regard are the following: Is it a bulky central tumor? Is there evidence of widespread metastatic disease, an obstructing mass, and/or tumor lysis? One final and critical aspect to consider is whether there are any patient- specific barriers to timely and reliable outpatient follow-up. If there is no evidence of rapid progression, bulky disease with threatened end-organ involvement, and/or issues with timely and reliable follow-up, then outpatient evaluation is often the best approach to ensure a comprehensive and well-coordinated effort on the patient’s behalf.

►Dr. Reese: Buprenorphine/naloxone was restarted without return of the symptoms. The patient was discharged home with an outpatient PET scan scheduled the following week. Unfortunately, the patient was unable to keep this appointment. Three weeks after hospital discharge, the patient presented again to the emergency department with gradually worsening altered mental status, confusion, visual hallucinations, and myoclonic jerking of the arms and legs. Medication adherence was confirmed by the patient’s wife, resulting in a low concern for serotonin syndrome. Physical examination revealed confusion, dysarthria, diffuse, arrhythmic, myoclonic jerking in all extremities, asterixis in the upper extremities, and hyperreflexia.

A CT scan of the brain did not reveal an intracranial process. A spot electroencephalograph (EEG) and magnetic resonance image (MRI) of the brain were obtained. Dr. Weller, what is the utility of spot EEG vs 24-hour EEG? When might we choose one over the other?

►Dr. Weller: If a patient is persistently altered, then a spot EEG would be sufficient to capture a seizure if that is what is causing the patient’s altered mental status. However, if the patient’s mental status is waxing and waning, then that may warrant a 24-hour EEG because the patient may need to be monitored for longer periods to capture an event that is causing intermittent alterations in mental status.6 Additionally, patients who are acutely ill may require long-term monitoring for the purpose of treatment and outcome management.

►Dr. Reese: The spot EEG showed nearly continuous generalized slowing indicative of a diffuse encephalopathy. The MRI of the brain showed scattered, nonspecific periventricular T2 hyperintense foci, suggestive of advanced chronic microvascular ischemic changes.

A PET CT was obtained and revealed mildly fluorodeoxyglucose (FDG)-avid, enlarging nodules within the right lower lobe, which was suspicious for malignancy. There were no other areas of FDG avidity on the PET scan. Valproic acid was initiated for treatment of myoclonus with transition to clonazepam when no improvement was seen. After starting clonazepam, the patient’s condition stabilized.

Dr. Weller, given the additional history, how has your differential diagnosis changed?

►Dr. Weller: Given the patient’s laboratory findings, we can be quite sure that there is not a contributing metabolic process. The findings suggestive of metastatic cancer, along with the profound neurologic changes, are most concerning for a paraneoplastic syndrome. I would suggest biopsy and consideration of a lumbar puncture. One can also send serum markers, including a paraneoplastic antibody panel.

►Dr. Reese: Biopsy of the mass in his right lower lobe revealed squamous cell lung cancer. Dr. Schlechter and Dr. Rangachari, do you have a framework for the different forms of lung cancer?

►Dr. Schlechter/Dr. Rangachari: The 2 broad categories of lung cancer are small cell and non-small cell (NSCLC). Small cell lung cancer has a tight association with tobacco exposure and is often clinically defined by rapid, bulky progression (ie, weeks to months).^7,8 NSCLCs are also commonly seen in those with tobacco exposure, though not always. The main subgroups in this category are adenocarcinoma and squamous cell carcinoma. These cancers often evolve at a slower pace (ie, months to years).⁸ While small cell lung cancers are highgrade tumors and exquisitely sensitive to chemotherapy and radiation, NSCLCs tend to be less responsive to such therapies. The staging evaluation for either entity is the same and consists of defining localized vs metastatic disease.

►Dr. Reese: Because this patient had an MRI and PET scan that were both negative for metastatic disease, can we assume that this patient had stage I NSCLC?

►Dr. Schlechter/Dr. Rangachari: Not necessarily. While PET and MRI brain are exceptionally helpful in detecting distant metastases, they may over- or underestimate intrathoracic lymph node involvement by as much as 20%.⁹ As such, dedicated lymph node staging—either via bronchoscopy (endobronchial ultrasound) or surgically (mediastinoscopy) is indicated as lymph node involvement can significantly alter the stage, prognosis, and optimal therapeutic approach.^10,11

►Dr. Reese: After this diagnosis was made, the teams caring for this patient attributed his altered mental status to a paraneoplastic syndrome. What is a paraneoplastic syndrome, and how does a paraneoplastic syndrome from malignancy present? Does its presence worsen a patient’s prognosis?

►Dr. Schlechter/Dr. Rangachari: A paraneoplastic syndrome is defined by an immunologic response to the cancer that ends up erroneously targeting self-antigens. Paraneoplastic syndromes are associated with a broad array of clinical findings—from endocrinopathy to encephalopathy—and certain neoplasms are more commonly associated with these syndromes than others (eg, small cell lung cancer and thymoma). Further, severity and onset of a paraneoplastic syndrome does not correlate with the burden of visible disease—and the syndrome may predate the cancer diagnosis by months to years.¹¹ While treatment of the cancer affords the best hope of resolving the paraneoplastic syndrome, the cancer and the paraneoplastic process may have a discordant trajectory, with the paraneoplastic syndrome persisting even after the cancer is maximally treated. Although one might assume that paraneoplastic syndromes portend worse outcomes, in some cases, a presentation with the paraneoplastic syndrome may afford sooner detection of an otherwise occult/asymptomatic malignancy.

►Dr. Reese: The following week, the serum paraneoplastic antibody panel that tested for anti-Yo antibody, anti-Ri antibody,and anti-Hu antibody came back negative. Dr. Weller, what does this mean? Since we have yet to obtain a lumbar puncture, might his symptoms still be caused by a paraneoplastic syndrome?

►Dr. Weller: The negative serum test just means that he does not have antibodies to those 3 antibodies. There are now over 30 different paraneoplastic antibodies that have been discovered, and there are always more that are being discovered. So this negative test result does not exclude a paraneoplastic syndrome in the appropriate clinical context.12 Furthermore, the sensitivity and specificity for certain antibodies are different based upon source fluid, and cerebrospinal fluid testing would provide more diagnostic clarity. A negative test for paraneoplastic syndrome, by itself, would similarly not exclude a paraneoplastic syndrome. Often, empiric treatment is the best diagnostic option for paraneoplastic and autoimmune encephalopathies.

►Dr. Reese: The following week, the patient was discharged to rehabilitation with clonazepam for his symptoms and a scheduled follow-up. Given the patient’s frailty and medical comorbidities, thoracic surgery recommended consultation with radiation oncology. Dr. Schlechter and Dr. Rangachari, when do we decide to use radiation vs chemotherapy for someone with lung cancer?

►Dr. Schlechter/Dr. Rangachari: Patients with early stage, nonmetastatic NSCLC may not always be candidates for surgical resection on the basis of pulmonary function, other medical comorbidities (as in this case), anatomic considerations, and/or patient preference. In these cases, if there is lung-limited disease without lymph node involvement (ie, stage I/II NSCLC) and the patient is not felt to be an operative candidate, then alternatives to surgery include either radiation or ablation.13,14 As we care for an aging and comorbid population, evolving evidence suggests that well-selected patients with early stage disease undergoing these nonoperative approaches have roughly equivalent outcomes to those undergoing conventional surgical resection.13 In such cases, multidisciplinary consultation with a team having dedicated expertise in these various operative and nonoperative modalities is essential.

►Dr. Reese: The patient followed up with radiation oncology for consideration of radiation treatment, but his simulation CT scan showed some ground-glass opacity that were concerning for inflammation vs infection. The patient’s case was discussed at the multidisciplinary tumor board, and it was determined to treat him with antibiotics for a possible pneumonia before proceeding with radiation therapy. After he completed antibiotic treatment, he underwent 10 fractions of radiation treatment, which he tolerated well.

►Zachary Reese, MD, Chief Medical Resident, VABHS and Beth Israel Deaconess Medical Center (BIDMC):Dr. Weller, the differential diagnosis for altered mental status is quite broad. How does the presence of clonus change or focus your approach to altered mental status?

►Jason Weller, MD, Instructor of Neurology, Boston Medical Center (BMC) and VABHS:The presence of clonus does not significantly narrow the differential. It does, however, suggest a central component to the patient’s altered mental status. Specifically, it implies that the underlying process, whether systemic or neurologic, interferes with central nervous system (CNS) control of the neuromuscular system.¹ The differential is still quite broad and includes metabolic derangements (eg, uremia, electrolyte disturbances, hypercarbia, and thyroid dysfunction), medication toxicity from olanzapine or duloxetine, and vascular processes (eg, CNS vasculitis). Infectious etiologies, both within the CNS and systemically, can cause encephalopathy, as can autoimmune processes, such as immune-mediated encephalitis. Finally, primary neurologic conditions such as myoclonic epilepsy can be considered. Given the patient’s medical history, serotonin syndrome must be considered.

►Dr. Reese: Given the concern for serotonin syndrome, the admitting medical team discontinued the patient’s duloxetine. Dr. Weller, what is the pathophysiology of serotonin syndrome, and how is it diagnosed?

►Dr. Weller: Serotonin is ubiquitous throughout the body and brain. Serotonin syndrome is caused by excess endogenous or exogenous serotonin, and this is usually caused by a variety of medications. The symptoms range from tachycardia, agitation, and diaphoresis to sustained clonus, hyperthermia, and shock.^2,3 The extent of serotonin syndrome is typically thought to reflect the degree of serotonergic activity.⁴

Serotonin syndrome is a clinical diagnosis. While there are no tests that can confirm the diagnosis, the Hunter criteria can be used to assist with making the diagnosis.⁵ Per the Hunter criteria, a patient can be diagnosed with serotonin syndrome if they have taken a serotonergic agent and have at least 1 of the following: spontaneous clonus, inducible or ocular clonus with agitation or diaphoresis, tremor and hyperreflexia, or hypertonia with fever and clonus. This patient had taken duloxetine and had inducible clonus and diaphoresis, thus suggesting a diagnosis of serotonin syndrome.

►Dr. Reese: Aside from selective serotonin reuptake inhibitors (SSRIs), are there other medications that we typically prescribe that can cause serotonin syndrome?

►Dr. Weller: In addition to SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs), other commonly prescribed medications that can cause serotonin syndrome are 5-HT3 antagonists (eg, ondansetron), 5-HT agonists (eg, triptans), and opioids (eg, fentanyl and tramadol). There are also case reports of atypical antipsychotics (eg, olanzapine) causing serotonin syndrome because of their antagonism of the 5-HT2 and 5-HT3 receptors.² Additionally, linezolid is commonly overlooked as a cause of serotonin syndrome given its action as a monoamine oxidase inhibitor.⁴ In this patient, it would be prudent to discontinue olanzapine and duloxetine.

►Dr. Reese: Duloxetine, olanzapine, and buprenorphine/naloxone were discontinuedgiven concern for serotonin syndrome. Although there are not strong data that buprenorphine/ naloxone can cause serotonin syndrome, the team discontinued the medication in case it might be contributing to the patient’s encephalopathy, while closely monitoring the patient for withdrawal. There was a rapid improvement in the patient’s symptoms over the 24 hours after discontinuation of the 3 medications.

As part of the initial workup, the patient received a computed tomography (CT) scan of his chest to follow up pulmonary nodules identified 16 months prior. The CT scan showed interval growth of the pulmonary nodules in the right lower lobe to 2 cm with extension into the major fissure, which was concerning for malignancy. Plans were made for an outpatient positron emission tomography (PET) scan after hospital discharge.

Dr. Schlechter and Dr. Rangachari, what factors can help us determine whether or not further workup of a malignancy should occur before discharge or can be deferred to the outpatient setting?

►Benjamin Schlechter, MD, Instructor in Medicine, BIDMC; and Deepa Rangachari, MD, Assistant Professor of Medicine, BIDMC: Key considerations in this domain include rapidity of growth and any threat to critical end-organ function (ie, brain, heart, lungs, kidney, and liver). If the malignancy is bulky and/or rapidly progressing to the point that the patient has significant symptoms burden and/or end-organ dysfunction, then initiating the evaluation as an inpatient may be necessary. For suspected intrathoracic malignancies, considering whether this may be a high-grade process (ie, small cell lung cancer) is often a vital branch point. Key considerations in this regard are the following: Is it a bulky central tumor? Is there evidence of widespread metastatic disease, an obstructing mass, and/or tumor lysis? One final and critical aspect to consider is whether there are any patient- specific barriers to timely and reliable outpatient follow-up. If there is no evidence of rapid progression, bulky disease with threatened end-organ involvement, and/or issues with timely and reliable follow-up, then outpatient evaluation is often the best approach to ensure a comprehensive and well-coordinated effort on the patient’s behalf.

►Dr. Reese: Buprenorphine/naloxone was restarted without return of the symptoms. The patient was discharged home with an outpatient PET scan scheduled the following week. Unfortunately, the patient was unable to keep this appointment. Three weeks after hospital discharge, the patient presented again to the emergency department with gradually worsening altered mental status, confusion, visual hallucinations, and myoclonic jerking of the arms and legs. Medication adherence was confirmed by the patient’s wife, resulting in a low concern for serotonin syndrome. Physical examination revealed confusion, dysarthria, diffuse, arrhythmic, myoclonic jerking in all extremities, asterixis in the upper extremities, and hyperreflexia.

A CT scan of the brain did not reveal an intracranial process. A spot electroencephalograph (EEG) and magnetic resonance image (MRI) of the brain were obtained. Dr. Weller, what is the utility of spot EEG vs 24-hour EEG? When might we choose one over the other?

►Dr. Weller: If a patient is persistently altered, then a spot EEG would be sufficient to capture a seizure if that is what is causing the patient’s altered mental status. However, if the patient’s mental status is waxing and waning, then that may warrant a 24-hour EEG because the patient may need to be monitored for longer periods to capture an event that is causing intermittent alterations in mental status.6 Additionally, patients who are acutely ill may require long-term monitoring for the purpose of treatment and outcome management.

►Dr. Reese: The spot EEG showed nearly continuous generalized slowing indicative of a diffuse encephalopathy. The MRI of the brain showed scattered, nonspecific periventricular T2 hyperintense foci, suggestive of advanced chronic microvascular ischemic changes.

A PET CT was obtained and revealed mildly fluorodeoxyglucose (FDG)-avid, enlarging nodules within the right lower lobe, which was suspicious for malignancy. There were no other areas of FDG avidity on the PET scan. Valproic acid was initiated for treatment of myoclonus with transition to clonazepam when no improvement was seen. After starting clonazepam, the patient’s condition stabilized.

Dr. Weller, given the additional history, how has your differential diagnosis changed?

►Dr. Weller: Given the patient’s laboratory findings, we can be quite sure that there is not a contributing metabolic process. The findings suggestive of metastatic cancer, along with the profound neurologic changes, are most concerning for a paraneoplastic syndrome. I would suggest biopsy and consideration of a lumbar puncture. One can also send serum markers, including a paraneoplastic antibody panel.

►Dr. Reese: Biopsy of the mass in his right lower lobe revealed squamous cell lung cancer. Dr. Schlechter and Dr. Rangachari, do you have a framework for the different forms of lung cancer?

►Dr. Schlechter/Dr. Rangachari: The 2 broad categories of lung cancer are small cell and non-small cell (NSCLC). Small cell lung cancer has a tight association with tobacco exposure and is often clinically defined by rapid, bulky progression (ie, weeks to months).^7,8 NSCLCs are also commonly seen in those with tobacco exposure, though not always. The main subgroups in this category are adenocarcinoma and squamous cell carcinoma. These cancers often evolve at a slower pace (ie, months to years).⁸ While small cell lung cancers are highgrade tumors and exquisitely sensitive to chemotherapy and radiation, NSCLCs tend to be less responsive to such therapies. The staging evaluation for either entity is the same and consists of defining localized vs metastatic disease.

►Dr. Reese: Because this patient had an MRI and PET scan that were both negative for metastatic disease, can we assume that this patient had stage I NSCLC?

►Dr. Schlechter/Dr. Rangachari: Not necessarily. While PET and MRI brain are exceptionally helpful in detecting distant metastases, they may over- or underestimate intrathoracic lymph node involvement by as much as 20%.⁹ As such, dedicated lymph node staging—either via bronchoscopy (endobronchial ultrasound) or surgically (mediastinoscopy) is indicated as lymph node involvement can significantly alter the stage, prognosis, and optimal therapeutic approach.^10,11

►Dr. Reese: After this diagnosis was made, the teams caring for this patient attributed his altered mental status to a paraneoplastic syndrome. What is a paraneoplastic syndrome, and how does a paraneoplastic syndrome from malignancy present? Does its presence worsen a patient’s prognosis?

►Dr. Schlechter/Dr. Rangachari: A paraneoplastic syndrome is defined by an immunologic response to the cancer that ends up erroneously targeting self-antigens. Paraneoplastic syndromes are associated with a broad array of clinical findings—from endocrinopathy to encephalopathy—and certain neoplasms are more commonly associated with these syndromes than others (eg, small cell lung cancer and thymoma). Further, severity and onset of a paraneoplastic syndrome does not correlate with the burden of visible disease—and the syndrome may predate the cancer diagnosis by months to years.¹¹ While treatment of the cancer affords the best hope of resolving the paraneoplastic syndrome, the cancer and the paraneoplastic process may have a discordant trajectory, with the paraneoplastic syndrome persisting even after the cancer is maximally treated. Although one might assume that paraneoplastic syndromes portend worse outcomes, in some cases, a presentation with the paraneoplastic syndrome may afford sooner detection of an otherwise occult/asymptomatic malignancy.

►Dr. Reese: The following week, the serum paraneoplastic antibody panel that tested for anti-Yo antibody, anti-Ri antibody,and anti-Hu antibody came back negative. Dr. Weller, what does this mean? Since we have yet to obtain a lumbar puncture, might his symptoms still be caused by a paraneoplastic syndrome?

►Dr. Weller: The negative serum test just means that he does not have antibodies to those 3 antibodies. There are now over 30 different paraneoplastic antibodies that have been discovered, and there are always more that are being discovered. So this negative test result does not exclude a paraneoplastic syndrome in the appropriate clinical context.12 Furthermore, the sensitivity and specificity for certain antibodies are different based upon source fluid, and cerebrospinal fluid testing would provide more diagnostic clarity. A negative test for paraneoplastic syndrome, by itself, would similarly not exclude a paraneoplastic syndrome. Often, empiric treatment is the best diagnostic option for paraneoplastic and autoimmune encephalopathies.

►Dr. Reese: The following week, the patient was discharged to rehabilitation with clonazepam for his symptoms and a scheduled follow-up. Given the patient’s frailty and medical comorbidities, thoracic surgery recommended consultation with radiation oncology. Dr. Schlechter and Dr. Rangachari, when do we decide to use radiation vs chemotherapy for someone with lung cancer?

►Dr. Schlechter/Dr. Rangachari: Patients with early stage, nonmetastatic NSCLC may not always be candidates for surgical resection on the basis of pulmonary function, other medical comorbidities (as in this case), anatomic considerations, and/or patient preference. In these cases, if there is lung-limited disease without lymph node involvement (ie, stage I/II NSCLC) and the patient is not felt to be an operative candidate, then alternatives to surgery include either radiation or ablation.13,14 As we care for an aging and comorbid population, evolving evidence suggests that well-selected patients with early stage disease undergoing these nonoperative approaches have roughly equivalent outcomes to those undergoing conventional surgical resection.13 In such cases, multidisciplinary consultation with a team having dedicated expertise in these various operative and nonoperative modalities is essential.

►Dr. Reese: The patient followed up with radiation oncology for consideration of radiation treatment, but his simulation CT scan showed some ground-glass opacity that were concerning for inflammation vs infection. The patient’s case was discussed at the multidisciplinary tumor board, and it was determined to treat him with antibiotics for a possible pneumonia before proceeding with radiation therapy. After he completed antibiotic treatment, he underwent 10 fractions of radiation treatment, which he tolerated well.

►Zachary Reese, MD, Chief Medical Resident, VABHS and Beth Israel Deaconess Medical Center (BIDMC):Dr. Weller, the differential diagnosis for altered mental status is quite broad. How does the presence of clonus change or focus your approach to altered mental status?

►Jason Weller, MD, Instructor of Neurology, Boston Medical Center (BMC) and VABHS:The presence of clonus does not significantly narrow the differential. It does, however, suggest a central component to the patient’s altered mental status. Specifically, it implies that the underlying process, whether systemic or neurologic, interferes with central nervous system (CNS) control of the neuromuscular system.¹ The differential is still quite broad and includes metabolic derangements (eg, uremia, electrolyte disturbances, hypercarbia, and thyroid dysfunction), medication toxicity from olanzapine or duloxetine, and vascular processes (eg, CNS vasculitis). Infectious etiologies, both within the CNS and systemically, can cause encephalopathy, as can autoimmune processes, such as immune-mediated encephalitis. Finally, primary neurologic conditions such as myoclonic epilepsy can be considered. Given the patient’s medical history, serotonin syndrome must be considered.

►Dr. Reese: Given the concern for serotonin syndrome, the admitting medical team discontinued the patient’s duloxetine. Dr. Weller, what is the pathophysiology of serotonin syndrome, and how is it diagnosed?

►Dr. Weller: Serotonin is ubiquitous throughout the body and brain. Serotonin syndrome is caused by excess endogenous or exogenous serotonin, and this is usually caused by a variety of medications. The symptoms range from tachycardia, agitation, and diaphoresis to sustained clonus, hyperthermia, and shock.^2,3 The extent of serotonin syndrome is typically thought to reflect the degree of serotonergic activity.⁴

Serotonin syndrome is a clinical diagnosis. While there are no tests that can confirm the diagnosis, the Hunter criteria can be used to assist with making the diagnosis.⁵ Per the Hunter criteria, a patient can be diagnosed with serotonin syndrome if they have taken a serotonergic agent and have at least 1 of the following: spontaneous clonus, inducible or ocular clonus with agitation or diaphoresis, tremor and hyperreflexia, or hypertonia with fever and clonus. This patient had taken duloxetine and had inducible clonus and diaphoresis, thus suggesting a diagnosis of serotonin syndrome.

►Dr. Reese: Aside from selective serotonin reuptake inhibitors (SSRIs), are there other medications that we typically prescribe that can cause serotonin syndrome?

►Dr. Weller: In addition to SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs), other commonly prescribed medications that can cause serotonin syndrome are 5-HT3 antagonists (eg, ondansetron), 5-HT agonists (eg, triptans), and opioids (eg, fentanyl and tramadol). There are also case reports of atypical antipsychotics (eg, olanzapine) causing serotonin syndrome because of their antagonism of the 5-HT2 and 5-HT3 receptors.² Additionally, linezolid is commonly overlooked as a cause of serotonin syndrome given its action as a monoamine oxidase inhibitor.⁴ In this patient, it would be prudent to discontinue olanzapine and duloxetine.

►Dr. Reese: Duloxetine, olanzapine, and buprenorphine/naloxone were discontinuedgiven concern for serotonin syndrome. Although there are not strong data that buprenorphine/ naloxone can cause serotonin syndrome, the team discontinued the medication in case it might be contributing to the patient’s encephalopathy, while closely monitoring the patient for withdrawal. There was a rapid improvement in the patient’s symptoms over the 24 hours after discontinuation of the 3 medications.

As part of the initial workup, the patient received a computed tomography (CT) scan of his chest to follow up pulmonary nodules identified 16 months prior. The CT scan showed interval growth of the pulmonary nodules in the right lower lobe to 2 cm with extension into the major fissure, which was concerning for malignancy. Plans were made for an outpatient positron emission tomography (PET) scan after hospital discharge.

Dr. Schlechter and Dr. Rangachari, what factors can help us determine whether or not further workup of a malignancy should occur before discharge or can be deferred to the outpatient setting?

►Benjamin Schlechter, MD, Instructor in Medicine, BIDMC; and Deepa Rangachari, MD, Assistant Professor of Medicine, BIDMC: Key considerations in this domain include rapidity of growth and any threat to critical end-organ function (ie, brain, heart, lungs, kidney, and liver). If the malignancy is bulky and/or rapidly progressing to the point that the patient has significant symptoms burden and/or end-organ dysfunction, then initiating the evaluation as an inpatient may be necessary. For suspected intrathoracic malignancies, considering whether this may be a high-grade process (ie, small cell lung cancer) is often a vital branch point. Key considerations in this regard are the following: Is it a bulky central tumor? Is there evidence of widespread metastatic disease, an obstructing mass, and/or tumor lysis? One final and critical aspect to consider is whether there are any patient- specific barriers to timely and reliable outpatient follow-up. If there is no evidence of rapid progression, bulky disease with threatened end-organ involvement, and/or issues with timely and reliable follow-up, then outpatient evaluation is often the best approach to ensure a comprehensive and well-coordinated effort on the patient’s behalf.

►Dr. Reese: Buprenorphine/naloxone was restarted without return of the symptoms. The patient was discharged home with an outpatient PET scan scheduled the following week. Unfortunately, the patient was unable to keep this appointment. Three weeks after hospital discharge, the patient presented again to the emergency department with gradually worsening altered mental status, confusion, visual hallucinations, and myoclonic jerking of the arms and legs. Medication adherence was confirmed by the patient’s wife, resulting in a low concern for serotonin syndrome. Physical examination revealed confusion, dysarthria, diffuse, arrhythmic, myoclonic jerking in all extremities, asterixis in the upper extremities, and hyperreflexia.

A CT scan of the brain did not reveal an intracranial process. A spot electroencephalograph (EEG) and magnetic resonance image (MRI) of the brain were obtained. Dr. Weller, what is the utility of spot EEG vs 24-hour EEG? When might we choose one over the other?

►Dr. Weller: If a patient is persistently altered, then a spot EEG would be sufficient to capture a seizure if that is what is causing the patient’s altered mental status. However, if the patient’s mental status is waxing and waning, then that may warrant a 24-hour EEG because the patient may need to be monitored for longer periods to capture an event that is causing intermittent alterations in mental status.6 Additionally, patients who are acutely ill may require long-term monitoring for the purpose of treatment and outcome management.

►Dr. Reese: The spot EEG showed nearly continuous generalized slowing indicative of a diffuse encephalopathy. The MRI of the brain showed scattered, nonspecific periventricular T2 hyperintense foci, suggestive of advanced chronic microvascular ischemic changes.

A PET CT was obtained and revealed mildly fluorodeoxyglucose (FDG)-avid, enlarging nodules within the right lower lobe, which was suspicious for malignancy. There were no other areas of FDG avidity on the PET scan. Valproic acid was initiated for treatment of myoclonus with transition to clonazepam when no improvement was seen. After starting clonazepam, the patient’s condition stabilized.

Dr. Weller, given the additional history, how has your differential diagnosis changed?

►Dr. Weller: Given the patient’s laboratory findings, we can be quite sure that there is not a contributing metabolic process. The findings suggestive of metastatic cancer, along with the profound neurologic changes, are most concerning for a paraneoplastic syndrome. I would suggest biopsy and consideration of a lumbar puncture. One can also send serum markers, including a paraneoplastic antibody panel.

►Dr. Reese: Biopsy of the mass in his right lower lobe revealed squamous cell lung cancer. Dr. Schlechter and Dr. Rangachari, do you have a framework for the different forms of lung cancer?

►Dr. Schlechter/Dr. Rangachari: The 2 broad categories of lung cancer are small cell and non-small cell (NSCLC). Small cell lung cancer has a tight association with tobacco exposure and is often clinically defined by rapid, bulky progression (ie, weeks to months).^7,8 NSCLCs are also commonly seen in those with tobacco exposure, though not always. The main subgroups in this category are adenocarcinoma and squamous cell carcinoma. These cancers often evolve at a slower pace (ie, months to years).⁸ While small cell lung cancers are highgrade tumors and exquisitely sensitive to chemotherapy and radiation, NSCLCs tend to be less responsive to such therapies. The staging evaluation for either entity is the same and consists of defining localized vs metastatic disease.

►Dr. Reese: Because this patient had an MRI and PET scan that were both negative for metastatic disease, can we assume that this patient had stage I NSCLC?

►Dr. Schlechter/Dr. Rangachari: Not necessarily. While PET and MRI brain are exceptionally helpful in detecting distant metastases, they may over- or underestimate intrathoracic lymph node involvement by as much as 20%.⁹ As such, dedicated lymph node staging—either via bronchoscopy (endobronchial ultrasound) or surgically (mediastinoscopy) is indicated as lymph node involvement can significantly alter the stage, prognosis, and optimal therapeutic approach.^10,11

►Dr. Reese: After this diagnosis was made, the teams caring for this patient attributed his altered mental status to a paraneoplastic syndrome. What is a paraneoplastic syndrome, and how does a paraneoplastic syndrome from malignancy present? Does its presence worsen a patient’s prognosis?

►Dr. Schlechter/Dr. Rangachari: A paraneoplastic syndrome is defined by an immunologic response to the cancer that ends up erroneously targeting self-antigens. Paraneoplastic syndromes are associated with a broad array of clinical findings—from endocrinopathy to encephalopathy—and certain neoplasms are more commonly associated with these syndromes than others (eg, small cell lung cancer and thymoma). Further, severity and onset of a paraneoplastic syndrome does not correlate with the burden of visible disease—and the syndrome may predate the cancer diagnosis by months to years.¹¹ While treatment of the cancer affords the best hope of resolving the paraneoplastic syndrome, the cancer and the paraneoplastic process may have a discordant trajectory, with the paraneoplastic syndrome persisting even after the cancer is maximally treated. Although one might assume that paraneoplastic syndromes portend worse outcomes, in some cases, a presentation with the paraneoplastic syndrome may afford sooner detection of an otherwise occult/asymptomatic malignancy.

►Dr. Reese: The following week, the serum paraneoplastic antibody panel that tested for anti-Yo antibody, anti-Ri antibody,and anti-Hu antibody came back negative. Dr. Weller, what does this mean? Since we have yet to obtain a lumbar puncture, might his symptoms still be caused by a paraneoplastic syndrome?

►Dr. Weller: The negative serum test just means that he does not have antibodies to those 3 antibodies. There are now over 30 different paraneoplastic antibodies that have been discovered, and there are always more that are being discovered. So this negative test result does not exclude a paraneoplastic syndrome in the appropriate clinical context.12 Furthermore, the sensitivity and specificity for certain antibodies are different based upon source fluid, and cerebrospinal fluid testing would provide more diagnostic clarity. A negative test for paraneoplastic syndrome, by itself, would similarly not exclude a paraneoplastic syndrome. Often, empiric treatment is the best diagnostic option for paraneoplastic and autoimmune encephalopathies.

►Dr. Reese: The following week, the patient was discharged to rehabilitation with clonazepam for his symptoms and a scheduled follow-up. Given the patient’s frailty and medical comorbidities, thoracic surgery recommended consultation with radiation oncology. Dr. Schlechter and Dr. Rangachari, when do we decide to use radiation vs chemotherapy for someone with lung cancer?

►Dr. Schlechter/Dr. Rangachari: Patients with early stage, nonmetastatic NSCLC may not always be candidates for surgical resection on the basis of pulmonary function, other medical comorbidities (as in this case), anatomic considerations, and/or patient preference. In these cases, if there is lung-limited disease without lymph node involvement (ie, stage I/II NSCLC) and the patient is not felt to be an operative candidate, then alternatives to surgery include either radiation or ablation.13,14 As we care for an aging and comorbid population, evolving evidence suggests that well-selected patients with early stage disease undergoing these nonoperative approaches have roughly equivalent outcomes to those undergoing conventional surgical resection.13 In such cases, multidisciplinary consultation with a team having dedicated expertise in these various operative and nonoperative modalities is essential.

►Dr. Reese: The patient followed up with radiation oncology for consideration of radiation treatment, but his simulation CT scan showed some ground-glass opacity that were concerning for inflammation vs infection. The patient’s case was discussed at the multidisciplinary tumor board, and it was determined to treat him with antibiotics for a possible pneumonia before proceeding with radiation therapy. After he completed antibiotic treatment, he underwent 10 fractions of radiation treatment, which he tolerated well.

Schlaff WD, Ackerman RT, Al-Hendy A, et al. Elagolix for heavy menstrual bleeding in women with uterine fibroids. N Engl J Med. 2020;382:328-340.

Expert Commentary

Any women’s health care provider is extremely aware of how common uterine fibroids (leiomyomas) are in reproductive-aged women. Bleeding associated with such fibroids is a common source of medical morbidity and reduced quality of life for many patients. The mainstay treatment approach for such patients has been surgical, which over time has become minimally invasive. Finding a nonsurgical treatment for patients with fibroid-associated HMB is of huge importance. The recent failure of the selective progesterone receptor modulator ulipristal acetate to be approved by the US Food and Drug Administration (FDA) was a significant setback to finding an excellent option for medical management. A gonadotropin-releasing hormone (GnRH) antagonist like elagolix could become an incredibly important “arrow in the quiver” of women’s health clinicians.

Details about elagolix

As mentioned, elagolix was FDA approved in 2-dose regimens for the treatment of dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia associated with endometriosis. One would expect that such a GnRH antagonist would reduce or eliminate HMB in patients with fibroids, although formal study had never been undertaken. Previous studies of elagolix had shown the most common adverse reaction to be vasomotor symptoms—hot flashes and night sweats. In addition, the drug shows a dose-dependent decrease in bone mineral density (BMD), although its effect on long-term bone health and future fracture risk is unknown.¹

Study specifics. The current study by Schlaff and colleagues was performed including 3 arms: a placebo arm, an elagolix 300 mg twice daily arm, and a third arm that received elagolix 300 mg twice daily and hormonal “add-back” therapy in the form of estradiol 1 mg and norethindrone acetate 0.5 mg daily. The authors actually report on two phase 3 six-month trials that were identical, double-blind, and randomized in nature. Both trials involved approximately 400 women. About 70% of the study participants overall were black, and the average age was approximately 42 years (range, 18 to 51). At baseline, BMD scores were mostly in the normal range. HMB for inclusion was defined as a volume of more than 80 mL per month.

The primary end point was menstrual blood loss volume less than 80 mL in the final month and at least a 50% reduction in menstrual blood loss from baseline to the final month. In the placebo group, only 9% and 10%, respectively, met these criteria.

Continue to: Results...

Results. In the first study group, 84% of those receiving elagolix alone achieved the primary end point, while the group that received elagolix plus add-back therapy had 69% success.

In the second study, both the elagolix group and the add-back group showed that 77% of patients met the primary end point criteria.

The incidences of hot flashes in the elagolix-alone groups were 64% and 43%, respectively, while with add-back therapy, they were 20% in both trials. In the placebo groups, 9% and 4% of participants reported hot flashes. At 6 months, the elagolix-only groups in both trials lost more BMD than the placebo groups, while BMD loss in both add-back groups was not statistically significant from the placebo groups.

Study strengths

Schlaff and colleagues conducted a very well-designed study. The two phase 3 clinical trials in preparation for drug approval were thorough and well reported. The authors are to be commended for including nearly 70% black women as study participants, since this is a racial group known to be affected by HMB resulting from fibroids.

Another strength was the addition of add-back therapy to the doses of elagolix. Concerns about bone loss from a health perspective and vasomotor symptoms from a quality-of-life perspective are not insignificant with elagolix-alone treatment, and proof that add-back therapy significantly diminishes or attenuates the efficacy of this entity is extremely important.

Schlaff WD, Ackerman RT, Al-Hendy A, et al. Elagolix for heavy menstrual bleeding in women with uterine fibroids. N Engl J Med. 2020;382:328-340.

Expert Commentary

Any women’s health care provider is extremely aware of how common uterine fibroids (leiomyomas) are in reproductive-aged women. Bleeding associated with such fibroids is a common source of medical morbidity and reduced quality of life for many patients. The mainstay treatment approach for such patients has been surgical, which over time has become minimally invasive. Finding a nonsurgical treatment for patients with fibroid-associated HMB is of huge importance. The recent failure of the selective progesterone receptor modulator ulipristal acetate to be approved by the US Food and Drug Administration (FDA) was a significant setback to finding an excellent option for medical management. A gonadotropin-releasing hormone (GnRH) antagonist like elagolix could become an incredibly important “arrow in the quiver” of women’s health clinicians.

Details about elagolix

As mentioned, elagolix was FDA approved in 2-dose regimens for the treatment of dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia associated with endometriosis. One would expect that such a GnRH antagonist would reduce or eliminate HMB in patients with fibroids, although formal study had never been undertaken. Previous studies of elagolix had shown the most common adverse reaction to be vasomotor symptoms—hot flashes and night sweats. In addition, the drug shows a dose-dependent decrease in bone mineral density (BMD), although its effect on long-term bone health and future fracture risk is unknown.¹

Study specifics. The current study by Schlaff and colleagues was performed including 3 arms: a placebo arm, an elagolix 300 mg twice daily arm, and a third arm that received elagolix 300 mg twice daily and hormonal “add-back” therapy in the form of estradiol 1 mg and norethindrone acetate 0.5 mg daily. The authors actually report on two phase 3 six-month trials that were identical, double-blind, and randomized in nature. Both trials involved approximately 400 women. About 70% of the study participants overall were black, and the average age was approximately 42 years (range, 18 to 51). At baseline, BMD scores were mostly in the normal range. HMB for inclusion was defined as a volume of more than 80 mL per month.

The primary end point was menstrual blood loss volume less than 80 mL in the final month and at least a 50% reduction in menstrual blood loss from baseline to the final month. In the placebo group, only 9% and 10%, respectively, met these criteria.

Continue to: Results...

Results. In the first study group, 84% of those receiving elagolix alone achieved the primary end point, while the group that received elagolix plus add-back therapy had 69% success.

In the second study, both the elagolix group and the add-back group showed that 77% of patients met the primary end point criteria.

The incidences of hot flashes in the elagolix-alone groups were 64% and 43%, respectively, while with add-back therapy, they were 20% in both trials. In the placebo groups, 9% and 4% of participants reported hot flashes. At 6 months, the elagolix-only groups in both trials lost more BMD than the placebo groups, while BMD loss in both add-back groups was not statistically significant from the placebo groups.

Study strengths

Schlaff and colleagues conducted a very well-designed study. The two phase 3 clinical trials in preparation for drug approval were thorough and well reported. The authors are to be commended for including nearly 70% black women as study participants, since this is a racial group known to be affected by HMB resulting from fibroids.

Another strength was the addition of add-back therapy to the doses of elagolix. Concerns about bone loss from a health perspective and vasomotor symptoms from a quality-of-life perspective are not insignificant with elagolix-alone treatment, and proof that add-back therapy significantly diminishes or attenuates the efficacy of this entity is extremely important.

Schlaff WD, Ackerman RT, Al-Hendy A, et al. Elagolix for heavy menstrual bleeding in women with uterine fibroids. N Engl J Med. 2020;382:328-340.

Expert Commentary

Any women’s health care provider is extremely aware of how common uterine fibroids (leiomyomas) are in reproductive-aged women. Bleeding associated with such fibroids is a common source of medical morbidity and reduced quality of life for many patients. The mainstay treatment approach for such patients has been surgical, which over time has become minimally invasive. Finding a nonsurgical treatment for patients with fibroid-associated HMB is of huge importance. The recent failure of the selective progesterone receptor modulator ulipristal acetate to be approved by the US Food and Drug Administration (FDA) was a significant setback to finding an excellent option for medical management. A gonadotropin-releasing hormone (GnRH) antagonist like elagolix could become an incredibly important “arrow in the quiver” of women’s health clinicians.

Details about elagolix

As mentioned, elagolix was FDA approved in 2-dose regimens for the treatment of dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia associated with endometriosis. One would expect that such a GnRH antagonist would reduce or eliminate HMB in patients with fibroids, although formal study had never been undertaken. Previous studies of elagolix had shown the most common adverse reaction to be vasomotor symptoms—hot flashes and night sweats. In addition, the drug shows a dose-dependent decrease in bone mineral density (BMD), although its effect on long-term bone health and future fracture risk is unknown.¹

Study specifics. The current study by Schlaff and colleagues was performed including 3 arms: a placebo arm, an elagolix 300 mg twice daily arm, and a third arm that received elagolix 300 mg twice daily and hormonal “add-back” therapy in the form of estradiol 1 mg and norethindrone acetate 0.5 mg daily. The authors actually report on two phase 3 six-month trials that were identical, double-blind, and randomized in nature. Both trials involved approximately 400 women. About 70% of the study participants overall were black, and the average age was approximately 42 years (range, 18 to 51). At baseline, BMD scores were mostly in the normal range. HMB for inclusion was defined as a volume of more than 80 mL per month.

The primary end point was menstrual blood loss volume less than 80 mL in the final month and at least a 50% reduction in menstrual blood loss from baseline to the final month. In the placebo group, only 9% and 10%, respectively, met these criteria.

Continue to: Results...

Results. In the first study group, 84% of those receiving elagolix alone achieved the primary end point, while the group that received elagolix plus add-back therapy had 69% success.

In the second study, both the elagolix group and the add-back group showed that 77% of patients met the primary end point criteria.

The incidences of hot flashes in the elagolix-alone groups were 64% and 43%, respectively, while with add-back therapy, they were 20% in both trials. In the placebo groups, 9% and 4% of participants reported hot flashes. At 6 months, the elagolix-only groups in both trials lost more BMD than the placebo groups, while BMD loss in both add-back groups was not statistically significant from the placebo groups.

Study strengths

Schlaff and colleagues conducted a very well-designed study. The two phase 3 clinical trials in preparation for drug approval were thorough and well reported. The authors are to be commended for including nearly 70% black women as study participants, since this is a racial group known to be affected by HMB resulting from fibroids.

Another strength was the addition of add-back therapy to the doses of elagolix. Concerns about bone loss from a health perspective and vasomotor symptoms from a quality-of-life perspective are not insignificant with elagolix-alone treatment, and proof that add-back therapy significantly diminishes or attenuates the efficacy of this entity is extremely important.

The sexually transmitted disease (STD) epidemic in the United States is intensifying, and it disproportionately impacts high-risk communities. In 2018, rates of reportable STDs, including syphilis and Neisseria gonorrhoeae and Chlamydia trachomatis infections, reached an all-time high.¹ That year, there were 1.8 million cases of chlamydia (increased 19% since 2014), 583,405 cases of gonorrhea (increased 63% since 2014), and 35,063 cases of primary and secondary syphilis (71% increase from 2014).¹

Cases of newborn syphilis have more than doubled in 4 years, with rates reaching a 20-year high.¹

This surge has not received the attention it deserves given the broad-reaching impact of these infections on women’s health and maternal-child health.² As ObGyns, we are on the front line, and we need to be engaged in evidence-based strategies and population-based health initiatives to expedite diagnoses and treatment and to reduce the ongoing spread of these infections.

Disparities exist and continue to fuel this epidemic

The STD burden is disproportionately high among reproductive-aged women, and half of all reported STDs occur in women aged 15 to 24 years. African American women have rates up to 12 times higher than white women.^3,4 Substantial geographic variability also exists, with the South, Southeast, and West having some of the highest STD rates.

These disparities are fueled by inequalities in socioeconomic status (SES), including employment, insurance, education, incarceration, stress/trauma exposure, and discrimination.^5-7 Those with lower SES often have trouble accessing and affording quality health care, including sexual health services. Access to quality health care, including STD prevention and treatment, that meets the needs of lower SES populations is key to reducing STD disparities in the United States; however, access likely will be insufficient unless the structural inequities that drive these disparities are addressed.

Clinical consequences for women, infants, and mothers

STDs are most prevalent among reproductive-aged women and can lead to pelvic inflammatory disease, infertility, ectopic pregnancy,^4,8 and increased risk of acquiring human immunodeficiency virus (HIV). STDs during pregnancy present additional consequences. Congenital syphilis is perhaps the most salient, with neonates experiencing substantial disability or death.

In addition, STDs contribute to overall peripartum and long-term adverse health outcomes.^4,9,10 Untreated chlamydia infection, for example, is associated with neonatal pneumonia, neonatal conjunctivitis, low birth weight, premature rupture of membranes, preterm labor, and postpartum endometritis.^2,11 Untreated gonorrhea is linked to disseminated gonococcal infection in the newborn, neonatal conjunctivitis, low birth weight, miscarriage, premature rupture of membranes, preterm labor, and chorioamnionitis.^2,12

As preterm birth is the leading cause of infant morbidity and mortality and disproportionately affects African American women and women in the southeastern United States,¹³ there is a critical public heath need to improve STD screening, treatment, and prevention of reinfection among high-risk pregnant women.

Quality clinical services for STDs: Areas for focus

More and more, STDs are being diagnosed in primary care settings. In January 2020, the Centers for Disease Control and Prevention (CDC) released a document, referred to as STD QCS (quality clinical services), that outlines recommendations for basic and specialty-level STD clinical services.¹⁴ ObGyns and other clinicians who provide primary care should meet the basic recommendations as a minimum.

The STD QCS outlines 8 recommendation areas: sexual history and physical examination, prevention, screening, partner services, evaluation of STD-related conditions, laboratory, treatment, and referral to a specialist for complex STD or STD-related conditions.¹⁴ These recommendations can be used by providers, managers, advocates, and others working to implement the highest-quality STD clinical services. Below are key areas that can be addressed in ObGyn practice.

Continue to: Sexual history and physical examination...

Sexual history and physical examination

A complete sexual history and risk assessment should be performed at a complete initial or annual visit and as indicated. Routinely updating the sexual history and risk assessment is important to normalize these questions within the frame of the person’s overall health, and it may be valuable in reducing stigma. This routine approach may be important particularly for younger patients and others whose risk for STDs may change frequently and dramatically.

Creating a safe space that permits privacy and assurance of confidentiality may help build trust and set the stage for disclosure. The American College of Obstetricians and Gynecologists recommends that all young people have time alone without parents for confidential counseling and discussion.¹⁵ All states allow minors to consent for STD services themselves, although 11 states limit this to those beyond a certain age.¹⁶

The CDC recommends using the 5 P’s—partners, practices, protection, past history of STDs, and prevention of pregnancy—as a guide for discussion.¹⁴ ObGyns are more likely than other providers to perform this screening routinely. While a pelvic examination should be available for STD evaluation as needed, it is not required for routine screening.

Prevention

ObGyns should employ several recommendations for STD prevention. These include providing or referring patients for vaccination against hepatitis B and human papillomavirus and providing brief STD/HIV prevention counseling along with contraceptive counseling. ObGyns should be familiar with HIV pre-exposure prophylaxis (PrEP) and nonoccupational postexposure prophylaxis (nPEP) and provide risk assessment, education, and referral or link to HIV care. Providing these services would improve access to care and further remove barriers to care. ObGyns also could consider providing condoms in their offices.¹⁴

Screening

STD screening of women at risk is critical since more than 80% of infected women are asymptomatic.⁸ Because young people are disproportionately experiencing STDs, annual screening for chlamydia and gonorrhea is recommended for women younger than 25 years. For women older than 25, those at increased risk can be screened.

Risk factors for chlamydia infection include having new or multiple sex partners, sex partners with concurrent partners, or sex partners who have an STD. For gonorrhea, risk factors include living in a high-morbidity area, having a previous or coexisting STD, new or multiple sex partners, inconsistent condom use in people who are not in a mutually monogamous relationship, and exchanging sex for money or drugs. Screening for syphilis in nonpregnant women is recommended for those who have had any sexual activity with a person recently diagnosed with syphilis or those who personally display signs or symptoms of infection.¹⁷

STD screening is especially important for pregnant women, and treatment of infections may improve pregnancy outcomes. The CDC recommends screening at the first prenatal care visit for chlamydia and gonorrhea in pregnant women younger than 25 years of age and in older pregnant women at increased risk; women younger than 25 years or at continued high risk should be rescreened in their third trimester. The CDC recommends screening all women for syphilis at their first prenatal care visit and rescreening those at high risk in the third trimester and at delivery (TABLE).¹⁸

Continue to: Partner services...

Partner services

Clearly outlined partner management services is paramount for preventing STD reinfection.¹⁴ Reinfection rates for chlamydia and gonorrhea among young women are high and vary by study population.¹⁹ At a minimum, ObGyns should counsel patients with an STD that their partner(s) should be notified and encouraged to seek services.

For states in which it is legal, expedited partner therapy (EPT)—the clinician provides medication for the partner without seeing the partner—should be provided for chlamydia or gonorrhea if the partner is unlikely to access timely care. EPT is legal in most states. (To check the legal status of EPT in your state, visit https://www.cdc.gov/std/ept/legal/default.htm.) Research is needed to evaluate optimal strategies for effective implementation of EPT services in different clinical settings.

Laboratory tests

ObGyns should be able to provide a wide range of laboratory evaluations (for example, a nucleic acid amplification test [NAAT] for genital chlamydia and gonorrhea, quantitative nontreponemal serologic test for syphilis, treponemal serologic test for syphilis) that can be ordered for screening or diagnostic purposes. To improve rates of recommended screening, consider having clinic-level policies that support screening, such as standing orders, express or walk-in screening appointments, lab panels, and reflex testing.

Further, having rapid results or point-of-care testing available would help decrease lags in time to treatment. Delays in treatment are particularly important in lower-resource communities; thus, point-of-care testing may be especially valuable with immediate access to treatment on site.

Treatment

Adequate and timely treatment of STDs is critical to decrease sequelae and the likelihood of transmission to others. Treatment is evolving, particularly for gonorrhea. Over the past several years, gonorrhea has become resistant to 6 previously recommended treatment options.²⁰ Since 2015, the CDC recommends dual therapy for gonorrhea with an injection of ceftriaxone and oral azithromycin.

The first-line recommended treatments for bacterial STDs are listed in the TABLE. When possible, it is preferred to offer directly observed therapy at the time of the visit. This decreases the time to treatment and ensures that therapy is completed.

A call to action for ObGyns

Clinicians have multiple opportunities to address and reduce the surge of STDs in the United States. We play a critical role in screening, diagnosing, and treating patients, and it is thus imperative to be up-to-date on the recommended guidelines. Further, clinicians can advocate for more rapid testing modalities, with the goal of obtaining point-of-care testing results when possible and implementing strategies to improve partner treatment.

While a positive STD result may be associated with significant patient distress, it also may be an opportunity for enhancing the patient-provider relationship, coupling education with motivational approaches to help patients increase protective health behaviors.

It is critical to approach clinical care in a nonjudgmental manner to improve patients’ comfort in their relationship with the health care system. ●

The sexually transmitted disease (STD) epidemic in the United States is intensifying, and it disproportionately impacts high-risk communities. In 2018, rates of reportable STDs, including syphilis and Neisseria gonorrhoeae and Chlamydia trachomatis infections, reached an all-time high.¹ That year, there were 1.8 million cases of chlamydia (increased 19% since 2014), 583,405 cases of gonorrhea (increased 63% since 2014), and 35,063 cases of primary and secondary syphilis (71% increase from 2014).¹

Cases of newborn syphilis have more than doubled in 4 years, with rates reaching a 20-year high.¹

This surge has not received the attention it deserves given the broad-reaching impact of these infections on women’s health and maternal-child health.² As ObGyns, we are on the front line, and we need to be engaged in evidence-based strategies and population-based health initiatives to expedite diagnoses and treatment and to reduce the ongoing spread of these infections.

Disparities exist and continue to fuel this epidemic

The STD burden is disproportionately high among reproductive-aged women, and half of all reported STDs occur in women aged 15 to 24 years. African American women have rates up to 12 times higher than white women.^3,4 Substantial geographic variability also exists, with the South, Southeast, and West having some of the highest STD rates.

These disparities are fueled by inequalities in socioeconomic status (SES), including employment, insurance, education, incarceration, stress/trauma exposure, and discrimination.^5-7 Those with lower SES often have trouble accessing and affording quality health care, including sexual health services. Access to quality health care, including STD prevention and treatment, that meets the needs of lower SES populations is key to reducing STD disparities in the United States; however, access likely will be insufficient unless the structural inequities that drive these disparities are addressed.

Clinical consequences for women, infants, and mothers

STDs are most prevalent among reproductive-aged women and can lead to pelvic inflammatory disease, infertility, ectopic pregnancy,^4,8 and increased risk of acquiring human immunodeficiency virus (HIV). STDs during pregnancy present additional consequences. Congenital syphilis is perhaps the most salient, with neonates experiencing substantial disability or death.

In addition, STDs contribute to overall peripartum and long-term adverse health outcomes.^4,9,10 Untreated chlamydia infection, for example, is associated with neonatal pneumonia, neonatal conjunctivitis, low birth weight, premature rupture of membranes, preterm labor, and postpartum endometritis.^2,11 Untreated gonorrhea is linked to disseminated gonococcal infection in the newborn, neonatal conjunctivitis, low birth weight, miscarriage, premature rupture of membranes, preterm labor, and chorioamnionitis.^2,12

As preterm birth is the leading cause of infant morbidity and mortality and disproportionately affects African American women and women in the southeastern United States,¹³ there is a critical public heath need to improve STD screening, treatment, and prevention of reinfection among high-risk pregnant women.

Quality clinical services for STDs: Areas for focus

More and more, STDs are being diagnosed in primary care settings. In January 2020, the Centers for Disease Control and Prevention (CDC) released a document, referred to as STD QCS (quality clinical services), that outlines recommendations for basic and specialty-level STD clinical services.¹⁴ ObGyns and other clinicians who provide primary care should meet the basic recommendations as a minimum.

The STD QCS outlines 8 recommendation areas: sexual history and physical examination, prevention, screening, partner services, evaluation of STD-related conditions, laboratory, treatment, and referral to a specialist for complex STD or STD-related conditions.¹⁴ These recommendations can be used by providers, managers, advocates, and others working to implement the highest-quality STD clinical services. Below are key areas that can be addressed in ObGyn practice.

Continue to: Sexual history and physical examination...

Sexual history and physical examination

A complete sexual history and risk assessment should be performed at a complete initial or annual visit and as indicated. Routinely updating the sexual history and risk assessment is important to normalize these questions within the frame of the person’s overall health, and it may be valuable in reducing stigma. This routine approach may be important particularly for younger patients and others whose risk for STDs may change frequently and dramatically.

Creating a safe space that permits privacy and assurance of confidentiality may help build trust and set the stage for disclosure. The American College of Obstetricians and Gynecologists recommends that all young people have time alone without parents for confidential counseling and discussion.¹⁵ All states allow minors to consent for STD services themselves, although 11 states limit this to those beyond a certain age.¹⁶

The CDC recommends using the 5 P’s—partners, practices, protection, past history of STDs, and prevention of pregnancy—as a guide for discussion.¹⁴ ObGyns are more likely than other providers to perform this screening routinely. While a pelvic examination should be available for STD evaluation as needed, it is not required for routine screening.

Prevention

ObGyns should employ several recommendations for STD prevention. These include providing or referring patients for vaccination against hepatitis B and human papillomavirus and providing brief STD/HIV prevention counseling along with contraceptive counseling. ObGyns should be familiar with HIV pre-exposure prophylaxis (PrEP) and nonoccupational postexposure prophylaxis (nPEP) and provide risk assessment, education, and referral or link to HIV care. Providing these services would improve access to care and further remove barriers to care. ObGyns also could consider providing condoms in their offices.¹⁴

Screening

STD screening of women at risk is critical since more than 80% of infected women are asymptomatic.⁸ Because young people are disproportionately experiencing STDs, annual screening for chlamydia and gonorrhea is recommended for women younger than 25 years. For women older than 25, those at increased risk can be screened.

Risk factors for chlamydia infection include having new or multiple sex partners, sex partners with concurrent partners, or sex partners who have an STD. For gonorrhea, risk factors include living in a high-morbidity area, having a previous or coexisting STD, new or multiple sex partners, inconsistent condom use in people who are not in a mutually monogamous relationship, and exchanging sex for money or drugs. Screening for syphilis in nonpregnant women is recommended for those who have had any sexual activity with a person recently diagnosed with syphilis or those who personally display signs or symptoms of infection.¹⁷

STD screening is especially important for pregnant women, and treatment of infections may improve pregnancy outcomes. The CDC recommends screening at the first prenatal care visit for chlamydia and gonorrhea in pregnant women younger than 25 years of age and in older pregnant women at increased risk; women younger than 25 years or at continued high risk should be rescreened in their third trimester. The CDC recommends screening all women for syphilis at their first prenatal care visit and rescreening those at high risk in the third trimester and at delivery (TABLE).¹⁸

Continue to: Partner services...

Partner services

Clearly outlined partner management services is paramount for preventing STD reinfection.¹⁴ Reinfection rates for chlamydia and gonorrhea among young women are high and vary by study population.¹⁹ At a minimum, ObGyns should counsel patients with an STD that their partner(s) should be notified and encouraged to seek services.

For states in which it is legal, expedited partner therapy (EPT)—the clinician provides medication for the partner without seeing the partner—should be provided for chlamydia or gonorrhea if the partner is unlikely to access timely care. EPT is legal in most states. (To check the legal status of EPT in your state, visit https://www.cdc.gov/std/ept/legal/default.htm.) Research is needed to evaluate optimal strategies for effective implementation of EPT services in different clinical settings.

Laboratory tests

ObGyns should be able to provide a wide range of laboratory evaluations (for example, a nucleic acid amplification test [NAAT] for genital chlamydia and gonorrhea, quantitative nontreponemal serologic test for syphilis, treponemal serologic test for syphilis) that can be ordered for screening or diagnostic purposes. To improve rates of recommended screening, consider having clinic-level policies that support screening, such as standing orders, express or walk-in screening appointments, lab panels, and reflex testing.

Further, having rapid results or point-of-care testing available would help decrease lags in time to treatment. Delays in treatment are particularly important in lower-resource communities; thus, point-of-care testing may be especially valuable with immediate access to treatment on site.

Treatment

Adequate and timely treatment of STDs is critical to decrease sequelae and the likelihood of transmission to others. Treatment is evolving, particularly for gonorrhea. Over the past several years, gonorrhea has become resistant to 6 previously recommended treatment options.²⁰ Since 2015, the CDC recommends dual therapy for gonorrhea with an injection of ceftriaxone and oral azithromycin.

The first-line recommended treatments for bacterial STDs are listed in the TABLE. When possible, it is preferred to offer directly observed therapy at the time of the visit. This decreases the time to treatment and ensures that therapy is completed.

A call to action for ObGyns

Clinicians have multiple opportunities to address and reduce the surge of STDs in the United States. We play a critical role in screening, diagnosing, and treating patients, and it is thus imperative to be up-to-date on the recommended guidelines. Further, clinicians can advocate for more rapid testing modalities, with the goal of obtaining point-of-care testing results when possible and implementing strategies to improve partner treatment.

While a positive STD result may be associated with significant patient distress, it also may be an opportunity for enhancing the patient-provider relationship, coupling education with motivational approaches to help patients increase protective health behaviors.

It is critical to approach clinical care in a nonjudgmental manner to improve patients’ comfort in their relationship with the health care system. ●

The sexually transmitted disease (STD) epidemic in the United States is intensifying, and it disproportionately impacts high-risk communities. In 2018, rates of reportable STDs, including syphilis and Neisseria gonorrhoeae and Chlamydia trachomatis infections, reached an all-time high.¹ That year, there were 1.8 million cases of chlamydia (increased 19% since 2014), 583,405 cases of gonorrhea (increased 63% since 2014), and 35,063 cases of primary and secondary syphilis (71% increase from 2014).¹

Cases of newborn syphilis have more than doubled in 4 years, with rates reaching a 20-year high.¹

This surge has not received the attention it deserves given the broad-reaching impact of these infections on women’s health and maternal-child health.² As ObGyns, we are on the front line, and we need to be engaged in evidence-based strategies and population-based health initiatives to expedite diagnoses and treatment and to reduce the ongoing spread of these infections.

Disparities exist and continue to fuel this epidemic

The STD burden is disproportionately high among reproductive-aged women, and half of all reported STDs occur in women aged 15 to 24 years. African American women have rates up to 12 times higher than white women.^3,4 Substantial geographic variability also exists, with the South, Southeast, and West having some of the highest STD rates.

These disparities are fueled by inequalities in socioeconomic status (SES), including employment, insurance, education, incarceration, stress/trauma exposure, and discrimination.^5-7 Those with lower SES often have trouble accessing and affording quality health care, including sexual health services. Access to quality health care, including STD prevention and treatment, that meets the needs of lower SES populations is key to reducing STD disparities in the United States; however, access likely will be insufficient unless the structural inequities that drive these disparities are addressed.

Clinical consequences for women, infants, and mothers

STDs are most prevalent among reproductive-aged women and can lead to pelvic inflammatory disease, infertility, ectopic pregnancy,^4,8 and increased risk of acquiring human immunodeficiency virus (HIV). STDs during pregnancy present additional consequences. Congenital syphilis is perhaps the most salient, with neonates experiencing substantial disability or death.

In addition, STDs contribute to overall peripartum and long-term adverse health outcomes.^4,9,10 Untreated chlamydia infection, for example, is associated with neonatal pneumonia, neonatal conjunctivitis, low birth weight, premature rupture of membranes, preterm labor, and postpartum endometritis.^2,11 Untreated gonorrhea is linked to disseminated gonococcal infection in the newborn, neonatal conjunctivitis, low birth weight, miscarriage, premature rupture of membranes, preterm labor, and chorioamnionitis.^2,12

As preterm birth is the leading cause of infant morbidity and mortality and disproportionately affects African American women and women in the southeastern United States,¹³ there is a critical public heath need to improve STD screening, treatment, and prevention of reinfection among high-risk pregnant women.

Quality clinical services for STDs: Areas for focus

More and more, STDs are being diagnosed in primary care settings. In January 2020, the Centers for Disease Control and Prevention (CDC) released a document, referred to as STD QCS (quality clinical services), that outlines recommendations for basic and specialty-level STD clinical services.¹⁴ ObGyns and other clinicians who provide primary care should meet the basic recommendations as a minimum.

The STD QCS outlines 8 recommendation areas: sexual history and physical examination, prevention, screening, partner services, evaluation of STD-related conditions, laboratory, treatment, and referral to a specialist for complex STD or STD-related conditions.¹⁴ These recommendations can be used by providers, managers, advocates, and others working to implement the highest-quality STD clinical services. Below are key areas that can be addressed in ObGyn practice.

Continue to: Sexual history and physical examination...

Sexual history and physical examination

A complete sexual history and risk assessment should be performed at a complete initial or annual visit and as indicated. Routinely updating the sexual history and risk assessment is important to normalize these questions within the frame of the person’s overall health, and it may be valuable in reducing stigma. This routine approach may be important particularly for younger patients and others whose risk for STDs may change frequently and dramatically.

Creating a safe space that permits privacy and assurance of confidentiality may help build trust and set the stage for disclosure. The American College of Obstetricians and Gynecologists recommends that all young people have time alone without parents for confidential counseling and discussion.¹⁵ All states allow minors to consent for STD services themselves, although 11 states limit this to those beyond a certain age.¹⁶

The CDC recommends using the 5 P’s—partners, practices, protection, past history of STDs, and prevention of pregnancy—as a guide for discussion.¹⁴ ObGyns are more likely than other providers to perform this screening routinely. While a pelvic examination should be available for STD evaluation as needed, it is not required for routine screening.

Prevention

ObGyns should employ several recommendations for STD prevention. These include providing or referring patients for vaccination against hepatitis B and human papillomavirus and providing brief STD/HIV prevention counseling along with contraceptive counseling. ObGyns should be familiar with HIV pre-exposure prophylaxis (PrEP) and nonoccupational postexposure prophylaxis (nPEP) and provide risk assessment, education, and referral or link to HIV care. Providing these services would improve access to care and further remove barriers to care. ObGyns also could consider providing condoms in their offices.¹⁴

Screening

STD screening of women at risk is critical since more than 80% of infected women are asymptomatic.⁸ Because young people are disproportionately experiencing STDs, annual screening for chlamydia and gonorrhea is recommended for women younger than 25 years. For women older than 25, those at increased risk can be screened.

Risk factors for chlamydia infection include having new or multiple sex partners, sex partners with concurrent partners, or sex partners who have an STD. For gonorrhea, risk factors include living in a high-morbidity area, having a previous or coexisting STD, new or multiple sex partners, inconsistent condom use in people who are not in a mutually monogamous relationship, and exchanging sex for money or drugs. Screening for syphilis in nonpregnant women is recommended for those who have had any sexual activity with a person recently diagnosed with syphilis or those who personally display signs or symptoms of infection.¹⁷

STD screening is especially important for pregnant women, and treatment of infections may improve pregnancy outcomes. The CDC recommends screening at the first prenatal care visit for chlamydia and gonorrhea in pregnant women younger than 25 years of age and in older pregnant women at increased risk; women younger than 25 years or at continued high risk should be rescreened in their third trimester. The CDC recommends screening all women for syphilis at their first prenatal care visit and rescreening those at high risk in the third trimester and at delivery (TABLE).¹⁸

Continue to: Partner services...

Partner services

Clearly outlined partner management services is paramount for preventing STD reinfection.¹⁴ Reinfection rates for chlamydia and gonorrhea among young women are high and vary by study population.¹⁹ At a minimum, ObGyns should counsel patients with an STD that their partner(s) should be notified and encouraged to seek services.

For states in which it is legal, expedited partner therapy (EPT)—the clinician provides medication for the partner without seeing the partner—should be provided for chlamydia or gonorrhea if the partner is unlikely to access timely care. EPT is legal in most states. (To check the legal status of EPT in your state, visit https://www.cdc.gov/std/ept/legal/default.htm.) Research is needed to evaluate optimal strategies for effective implementation of EPT services in different clinical settings.

Laboratory tests

ObGyns should be able to provide a wide range of laboratory evaluations (for example, a nucleic acid amplification test [NAAT] for genital chlamydia and gonorrhea, quantitative nontreponemal serologic test for syphilis, treponemal serologic test for syphilis) that can be ordered for screening or diagnostic purposes. To improve rates of recommended screening, consider having clinic-level policies that support screening, such as standing orders, express or walk-in screening appointments, lab panels, and reflex testing.

Further, having rapid results or point-of-care testing available would help decrease lags in time to treatment. Delays in treatment are particularly important in lower-resource communities; thus, point-of-care testing may be especially valuable with immediate access to treatment on site.

Treatment

Adequate and timely treatment of STDs is critical to decrease sequelae and the likelihood of transmission to others. Treatment is evolving, particularly for gonorrhea. Over the past several years, gonorrhea has become resistant to 6 previously recommended treatment options.²⁰ Since 2015, the CDC recommends dual therapy for gonorrhea with an injection of ceftriaxone and oral azithromycin.

The first-line recommended treatments for bacterial STDs are listed in the TABLE. When possible, it is preferred to offer directly observed therapy at the time of the visit. This decreases the time to treatment and ensures that therapy is completed.

A call to action for ObGyns

Clinicians have multiple opportunities to address and reduce the surge of STDs in the United States. We play a critical role in screening, diagnosing, and treating patients, and it is thus imperative to be up-to-date on the recommended guidelines. Further, clinicians can advocate for more rapid testing modalities, with the goal of obtaining point-of-care testing results when possible and implementing strategies to improve partner treatment.

While a positive STD result may be associated with significant patient distress, it also may be an opportunity for enhancing the patient-provider relationship, coupling education with motivational approaches to help patients increase protective health behaviors.

It is critical to approach clinical care in a nonjudgmental manner to improve patients’ comfort in their relationship with the health care system. ●

Lung cancer experts in Europe issued highly considered recommendations for the management of lung cancer during the COVID-19 crisis, the main intention of which is to minimize the risk of patients getting infected by SARS-CoV-2 while in hospital receiving treatment.

The recommendations were published online April 3 in ESMO Open.

“We know that having cancer increases the risk of dying of COVID-19, although not necessarily the risk of getting the virus, and we also know that having lung cancer could increase the risk of pulmonary complications from SARS-CoV-2,” lead author Alfredo Addeo, MD, University Hospital of Geneva, Switzerland, told Medscape Medical News.

“But patients who are often in the hospital have a higher risk of catching the virus. So this paper is not about not giving necessary treatment, it’s about treating patients the best you can based on the area where you live and the resources you have and keeping patients away from the hospital as much as possible,” he added.

“The main message is, try to personalize the care you deliver,” Addeo said. “Rather than remain rigid about how you’ve been treating patients thus far, try to think outside the box and find a way to minimize the risk of infection, and, if you have to limit treatment, discuss the pros and cons of your treatment plan with the patient and make sure the message is given clearly.”

How much benefit?

The first general concept to keep in mind is: How likely is a patient to benefit from treatment?

“All regimens with a survival benefit should be maintained and prioritised whenever possible,” Addeo and colleagues observe. The other co-authors of the paper are Giuseppe Banna, MD, Ospedale Cannizzaro, Catania, Italy; Alessandra Curioni-Fontecedro, MD, University Hospital Zurich, Switzerland; and Alex Friedlaender, MD, University Hospital of Geneva.

For non–small cell lung cancer (NSCLC), neoadjuvant chemotherapy for locally advanced resectable disease and sequential/concurrent chemotherapy/radiation therapy for patients with stage III lung cancer – provided they have adequate respiratory function – should be started when possible and should not be stopped without justification, the authors point out.

This is also true for first-line therapy in patients with metastatic disease. Treatment should also not be stopped without good reason among patients already receiving maintenance immune checkpoint inhibitor therapy.

For small cell lung cancer (SCLC), both first-line treatment for extensive-stage disease as well as concurrent chemotherapy/radiotherapy for patients with limited-stage disease should be started when possible, again provided they have adequate respiratory function.

Palliative or stereotactic body radiotherapy (SBRT) delivered outside the lung should also be initiated when possible in SCLC patients.

The authors caution, however, that if palliative or SBRT outside the lung requires multiple visits to the hospital, treatment to the lung should be limited to cases with compression of airways or bleeding.

Oncologists should also try to start radiotherapy on day 1 of chemotherapy because then only 2 cycles will be needed; if radiotherapy is started with cycle 2 or is given sequentially, 3 cycles of treatment will be required.

“Fractions of SBRT could be reduced, depending on organ at risk (8 fractions to 5 or 3) while palliative RT [given] as a single fraction or two (8-10 Gy or 17 Gy, respectively) should be used where possible,” the authors observe.

Concurrent chemotherapy with radiotherapy for limited-stage disease should not be stopped without justification and nor should first-line treatment for metastatic SCLC, the authors continue.

Again, however, patients must have adequate respiratory function to receive or continue with concurrent chemotherapy and radiotherapy, they add.

For patients with stage III NSCLC, concurrent chemotherapy plus radiotherapy may be considered and given preferentially or not.

Similarly, oral rather than intravenous chemotherapy may be preferred for elderly NSCLC patients or for those with an ECOG performance status of 2 as well as for SCLC patients.
 

Delaying surgery

As a general principle, the use of neoadjuvant chemotherapy instead of adjuvant therapy following surgery can delay the need for immediate surgery. If surgery can be delayed, “the risk of a patient catching the virus several months from now might be less,” Addeo noted. Thus, treating patients upfront with chemotherapy is one tactic to consider in appropriate patients.

For NSCLC patients at high risk for COVID-19, adjuvant chemotherapy should be discussed and potentially withheld, the authors observe.

NSCLC patients at high risk for COVID-19 include those with comorbidities, such as cardiovascular or pulmonary disease, as well as patients who are 70 years of age and older.

Immunotherapy should also be discussed and possibly delayed for stage III NSCLC patients following concurrent chemotherapy and radiation, they add.

Maintenance pemetrexed also may be withheld for NSCLC patients, and intervals of immunotherapy may be prolonged (e.g., nivolumab every 4 weeks and pembrolizumab every 6 weeks).

Intervals of immunotherapy should be similarly prolonged for SCLC patients, they continue.

“Shorter duration of chemotherapy (e.g., four cycles of chemotherapy instead of six) should be discussed with patients and maintenance chemotherapy can be withheld,” the authors note.

Furthermore, “given the pandemic, it is highly likely that metastatic cancer patients will be less likely to be intubated or to be heavily ventilated compared to patients without any comorbidity,” Addeo explained.

“So we have to acknowledge that metastatic lung cancer patients will be at higher risk of dying due to severe pulmonary COVID-19 complications,” he added.

Therefore, third and further lines of chemotherapy in both NSCLC and SCLC patients at significant COVID-19 risk should not be initiated without having a good reason to do so.

“Prophylactic cranial irradiation (PCI) is still a matter of debate [in SCLC patients],” Addeo noted. “So the reasonable alternative is to do surveillance MRI, and, in 6 or 8 months, we can probably offer PCI more safely at that point,” he suggested, adding that radiation therapy to the brain should only be considered if a patient develops brain metastases.

The authors also suggest that thoracic consolidation radiotherapy for extensive stage SCLC should not be initiated unless there is good reason to do so.

Patients with family members or caregivers who have tested positive for COVID-19 should themselves be tested before or during any cancer treatment.

If patients themselves then test positive and are asymptomatic, “28 days of delay should be considered before (re)starting the treatment,” the authors advise.

However, two negative tests done 1 week apart should be carried out before starting or restarting treatment, they note.

The authors have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Lung cancer experts in Europe issued highly considered recommendations for the management of lung cancer during the COVID-19 crisis, the main intention of which is to minimize the risk of patients getting infected by SARS-CoV-2 while in hospital receiving treatment.

The recommendations were published online April 3 in ESMO Open.

“We know that having cancer increases the risk of dying of COVID-19, although not necessarily the risk of getting the virus, and we also know that having lung cancer could increase the risk of pulmonary complications from SARS-CoV-2,” lead author Alfredo Addeo, MD, University Hospital of Geneva, Switzerland, told Medscape Medical News.

“But patients who are often in the hospital have a higher risk of catching the virus. So this paper is not about not giving necessary treatment, it’s about treating patients the best you can based on the area where you live and the resources you have and keeping patients away from the hospital as much as possible,” he added.

“The main message is, try to personalize the care you deliver,” Addeo said. “Rather than remain rigid about how you’ve been treating patients thus far, try to think outside the box and find a way to minimize the risk of infection, and, if you have to limit treatment, discuss the pros and cons of your treatment plan with the patient and make sure the message is given clearly.”

How much benefit?

The first general concept to keep in mind is: How likely is a patient to benefit from treatment?

“All regimens with a survival benefit should be maintained and prioritised whenever possible,” Addeo and colleagues observe. The other co-authors of the paper are Giuseppe Banna, MD, Ospedale Cannizzaro, Catania, Italy; Alessandra Curioni-Fontecedro, MD, University Hospital Zurich, Switzerland; and Alex Friedlaender, MD, University Hospital of Geneva.

For non–small cell lung cancer (NSCLC), neoadjuvant chemotherapy for locally advanced resectable disease and sequential/concurrent chemotherapy/radiation therapy for patients with stage III lung cancer – provided they have adequate respiratory function – should be started when possible and should not be stopped without justification, the authors point out.

This is also true for first-line therapy in patients with metastatic disease. Treatment should also not be stopped without good reason among patients already receiving maintenance immune checkpoint inhibitor therapy.

For small cell lung cancer (SCLC), both first-line treatment for extensive-stage disease as well as concurrent chemotherapy/radiotherapy for patients with limited-stage disease should be started when possible, again provided they have adequate respiratory function.

Palliative or stereotactic body radiotherapy (SBRT) delivered outside the lung should also be initiated when possible in SCLC patients.

The authors caution, however, that if palliative or SBRT outside the lung requires multiple visits to the hospital, treatment to the lung should be limited to cases with compression of airways or bleeding.

Oncologists should also try to start radiotherapy on day 1 of chemotherapy because then only 2 cycles will be needed; if radiotherapy is started with cycle 2 or is given sequentially, 3 cycles of treatment will be required.

“Fractions of SBRT could be reduced, depending on organ at risk (8 fractions to 5 or 3) while palliative RT [given] as a single fraction or two (8-10 Gy or 17 Gy, respectively) should be used where possible,” the authors observe.

Concurrent chemotherapy with radiotherapy for limited-stage disease should not be stopped without justification and nor should first-line treatment for metastatic SCLC, the authors continue.

Again, however, patients must have adequate respiratory function to receive or continue with concurrent chemotherapy and radiotherapy, they add.

For patients with stage III NSCLC, concurrent chemotherapy plus radiotherapy may be considered and given preferentially or not.

Similarly, oral rather than intravenous chemotherapy may be preferred for elderly NSCLC patients or for those with an ECOG performance status of 2 as well as for SCLC patients.
 

Delaying surgery

As a general principle, the use of neoadjuvant chemotherapy instead of adjuvant therapy following surgery can delay the need for immediate surgery. If surgery can be delayed, “the risk of a patient catching the virus several months from now might be less,” Addeo noted. Thus, treating patients upfront with chemotherapy is one tactic to consider in appropriate patients.

For NSCLC patients at high risk for COVID-19, adjuvant chemotherapy should be discussed and potentially withheld, the authors observe.

NSCLC patients at high risk for COVID-19 include those with comorbidities, such as cardiovascular or pulmonary disease, as well as patients who are 70 years of age and older.

Immunotherapy should also be discussed and possibly delayed for stage III NSCLC patients following concurrent chemotherapy and radiation, they add.

Maintenance pemetrexed also may be withheld for NSCLC patients, and intervals of immunotherapy may be prolonged (e.g., nivolumab every 4 weeks and pembrolizumab every 6 weeks).

Intervals of immunotherapy should be similarly prolonged for SCLC patients, they continue.

“Shorter duration of chemotherapy (e.g., four cycles of chemotherapy instead of six) should be discussed with patients and maintenance chemotherapy can be withheld,” the authors note.

Furthermore, “given the pandemic, it is highly likely that metastatic cancer patients will be less likely to be intubated or to be heavily ventilated compared to patients without any comorbidity,” Addeo explained.

“So we have to acknowledge that metastatic lung cancer patients will be at higher risk of dying due to severe pulmonary COVID-19 complications,” he added.

Therefore, third and further lines of chemotherapy in both NSCLC and SCLC patients at significant COVID-19 risk should not be initiated without having a good reason to do so.

“Prophylactic cranial irradiation (PCI) is still a matter of debate [in SCLC patients],” Addeo noted. “So the reasonable alternative is to do surveillance MRI, and, in 6 or 8 months, we can probably offer PCI more safely at that point,” he suggested, adding that radiation therapy to the brain should only be considered if a patient develops brain metastases.

The authors also suggest that thoracic consolidation radiotherapy for extensive stage SCLC should not be initiated unless there is good reason to do so.

Patients with family members or caregivers who have tested positive for COVID-19 should themselves be tested before or during any cancer treatment.

If patients themselves then test positive and are asymptomatic, “28 days of delay should be considered before (re)starting the treatment,” the authors advise.

However, two negative tests done 1 week apart should be carried out before starting or restarting treatment, they note.

The authors have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Lung cancer experts in Europe issued highly considered recommendations for the management of lung cancer during the COVID-19 crisis, the main intention of which is to minimize the risk of patients getting infected by SARS-CoV-2 while in hospital receiving treatment.

The recommendations were published online April 3 in ESMO Open.

“We know that having cancer increases the risk of dying of COVID-19, although not necessarily the risk of getting the virus, and we also know that having lung cancer could increase the risk of pulmonary complications from SARS-CoV-2,” lead author Alfredo Addeo, MD, University Hospital of Geneva, Switzerland, told Medscape Medical News.

“But patients who are often in the hospital have a higher risk of catching the virus. So this paper is not about not giving necessary treatment, it’s about treating patients the best you can based on the area where you live and the resources you have and keeping patients away from the hospital as much as possible,” he added.

“The main message is, try to personalize the care you deliver,” Addeo said. “Rather than remain rigid about how you’ve been treating patients thus far, try to think outside the box and find a way to minimize the risk of infection, and, if you have to limit treatment, discuss the pros and cons of your treatment plan with the patient and make sure the message is given clearly.”

How much benefit?

The first general concept to keep in mind is: How likely is a patient to benefit from treatment?

“All regimens with a survival benefit should be maintained and prioritised whenever possible,” Addeo and colleagues observe. The other co-authors of the paper are Giuseppe Banna, MD, Ospedale Cannizzaro, Catania, Italy; Alessandra Curioni-Fontecedro, MD, University Hospital Zurich, Switzerland; and Alex Friedlaender, MD, University Hospital of Geneva.

For non–small cell lung cancer (NSCLC), neoadjuvant chemotherapy for locally advanced resectable disease and sequential/concurrent chemotherapy/radiation therapy for patients with stage III lung cancer – provided they have adequate respiratory function – should be started when possible and should not be stopped without justification, the authors point out.

This is also true for first-line therapy in patients with metastatic disease. Treatment should also not be stopped without good reason among patients already receiving maintenance immune checkpoint inhibitor therapy.

For small cell lung cancer (SCLC), both first-line treatment for extensive-stage disease as well as concurrent chemotherapy/radiotherapy for patients with limited-stage disease should be started when possible, again provided they have adequate respiratory function.

Palliative or stereotactic body radiotherapy (SBRT) delivered outside the lung should also be initiated when possible in SCLC patients.

The authors caution, however, that if palliative or SBRT outside the lung requires multiple visits to the hospital, treatment to the lung should be limited to cases with compression of airways or bleeding.

Oncologists should also try to start radiotherapy on day 1 of chemotherapy because then only 2 cycles will be needed; if radiotherapy is started with cycle 2 or is given sequentially, 3 cycles of treatment will be required.

“Fractions of SBRT could be reduced, depending on organ at risk (8 fractions to 5 or 3) while palliative RT [given] as a single fraction or two (8-10 Gy or 17 Gy, respectively) should be used where possible,” the authors observe.

Concurrent chemotherapy with radiotherapy for limited-stage disease should not be stopped without justification and nor should first-line treatment for metastatic SCLC, the authors continue.

Again, however, patients must have adequate respiratory function to receive or continue with concurrent chemotherapy and radiotherapy, they add.

For patients with stage III NSCLC, concurrent chemotherapy plus radiotherapy may be considered and given preferentially or not.

Similarly, oral rather than intravenous chemotherapy may be preferred for elderly NSCLC patients or for those with an ECOG performance status of 2 as well as for SCLC patients.
 

Delaying surgery

As a general principle, the use of neoadjuvant chemotherapy instead of adjuvant therapy following surgery can delay the need for immediate surgery. If surgery can be delayed, “the risk of a patient catching the virus several months from now might be less,” Addeo noted. Thus, treating patients upfront with chemotherapy is one tactic to consider in appropriate patients.

For NSCLC patients at high risk for COVID-19, adjuvant chemotherapy should be discussed and potentially withheld, the authors observe.

NSCLC patients at high risk for COVID-19 include those with comorbidities, such as cardiovascular or pulmonary disease, as well as patients who are 70 years of age and older.

Immunotherapy should also be discussed and possibly delayed for stage III NSCLC patients following concurrent chemotherapy and radiation, they add.

Maintenance pemetrexed also may be withheld for NSCLC patients, and intervals of immunotherapy may be prolonged (e.g., nivolumab every 4 weeks and pembrolizumab every 6 weeks).

Intervals of immunotherapy should be similarly prolonged for SCLC patients, they continue.

“Shorter duration of chemotherapy (e.g., four cycles of chemotherapy instead of six) should be discussed with patients and maintenance chemotherapy can be withheld,” the authors note.

Furthermore, “given the pandemic, it is highly likely that metastatic cancer patients will be less likely to be intubated or to be heavily ventilated compared to patients without any comorbidity,” Addeo explained.

“So we have to acknowledge that metastatic lung cancer patients will be at higher risk of dying due to severe pulmonary COVID-19 complications,” he added.

Therefore, third and further lines of chemotherapy in both NSCLC and SCLC patients at significant COVID-19 risk should not be initiated without having a good reason to do so.

“Prophylactic cranial irradiation (PCI) is still a matter of debate [in SCLC patients],” Addeo noted. “So the reasonable alternative is to do surveillance MRI, and, in 6 or 8 months, we can probably offer PCI more safely at that point,” he suggested, adding that radiation therapy to the brain should only be considered if a patient develops brain metastases.

The authors also suggest that thoracic consolidation radiotherapy for extensive stage SCLC should not be initiated unless there is good reason to do so.

Patients with family members or caregivers who have tested positive for COVID-19 should themselves be tested before or during any cancer treatment.

If patients themselves then test positive and are asymptomatic, “28 days of delay should be considered before (re)starting the treatment,” the authors advise.

However, two negative tests done 1 week apart should be carried out before starting or restarting treatment, they note.

The authors have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Approximately one-third of high-risk chronic lymphocytic leukemia (CLL) patients received chemoimmunotherapy that was not aligned with current CLL treatment recommendations, according to a study based upon data from the informCLL registry. In addition, low levels of prognostic marker testing in these patients was a concern.

Researchers assessed data from 840 enrolled CLL patients, of whom 459 (55%) were previously untreated, and 381 (45%) had relapsed/refractory disease. In terms of therapy, chemoimmunotherapy was more common in previously untreated patients, compared with relapsed/refractory patients (42% vs. 23%), whereas ibrutinib was more frequently used in relapsed/refractory vs. previously untreated patients (51% vs. 39%), according to the researchers.

Fluorescent in situ hybridization (FISH) testing, TP53 mutation, and immunoglobulin heavy chain somatic hypermutation biomarker testing were performed infrequently across all patients at registry enrollment, according to the authors.

Among patients who were tested, the rate of mutated TP53 was the same for previously untreated (14/54; 26%) and relapsed/refractory patients (9/35; 26%). In those patients who were tested, 34% with del(17p), a chromosomal deletion, and 26% of mutated TP53 patients received chemoimmunotherapy combinations. The authors stated that this was concerning in that it contradicts consensus guidelines based on data from several clinical studies. Chemoimmunotherapy is not recommended for these high-risk patients because of poor disease and survival outcomes with this treatment strategy, according to the authors.

“Current clinical practice is not keeping pace with recommendations and guidelines for prognostic

marker testing and subsequent selection of appropriate therapy,” the authors stated.

“Even with the approval of novel agents and updated guidelines, low rates of prognostic biomarker testing may lead to suboptimal therapy choices for patients with unknown risk status. In addition, we note that the presence of high-risk features (del(17p) and TP53) is unfortunately not translating to choosing the optimal therapy for these patients,” the researchers concluded.

The study was sponsored by an AbbVie Company and Janssen. The authors reported consulting and grants from these and other pharmaceutical companies.

mlesney@mdedge.com

SOURCE: Mato AR et al. Clin Lymphoma Myeloma Leuk. 2020;20(3):174-83.

Approximately one-third of high-risk chronic lymphocytic leukemia (CLL) patients received chemoimmunotherapy that was not aligned with current CLL treatment recommendations, according to a study based upon data from the informCLL registry. In addition, low levels of prognostic marker testing in these patients was a concern.

Researchers assessed data from 840 enrolled CLL patients, of whom 459 (55%) were previously untreated, and 381 (45%) had relapsed/refractory disease. In terms of therapy, chemoimmunotherapy was more common in previously untreated patients, compared with relapsed/refractory patients (42% vs. 23%), whereas ibrutinib was more frequently used in relapsed/refractory vs. previously untreated patients (51% vs. 39%), according to the researchers.

Fluorescent in situ hybridization (FISH) testing, TP53 mutation, and immunoglobulin heavy chain somatic hypermutation biomarker testing were performed infrequently across all patients at registry enrollment, according to the authors.

Among patients who were tested, the rate of mutated TP53 was the same for previously untreated (14/54; 26%) and relapsed/refractory patients (9/35; 26%). In those patients who were tested, 34% with del(17p), a chromosomal deletion, and 26% of mutated TP53 patients received chemoimmunotherapy combinations. The authors stated that this was concerning in that it contradicts consensus guidelines based on data from several clinical studies. Chemoimmunotherapy is not recommended for these high-risk patients because of poor disease and survival outcomes with this treatment strategy, according to the authors.

“Current clinical practice is not keeping pace with recommendations and guidelines for prognostic

marker testing and subsequent selection of appropriate therapy,” the authors stated.

“Even with the approval of novel agents and updated guidelines, low rates of prognostic biomarker testing may lead to suboptimal therapy choices for patients with unknown risk status. In addition, we note that the presence of high-risk features (del(17p) and TP53) is unfortunately not translating to choosing the optimal therapy for these patients,” the researchers concluded.

The study was sponsored by an AbbVie Company and Janssen. The authors reported consulting and grants from these and other pharmaceutical companies.

mlesney@mdedge.com

SOURCE: Mato AR et al. Clin Lymphoma Myeloma Leuk. 2020;20(3):174-83.

Approximately one-third of high-risk chronic lymphocytic leukemia (CLL) patients received chemoimmunotherapy that was not aligned with current CLL treatment recommendations, according to a study based upon data from the informCLL registry. In addition, low levels of prognostic marker testing in these patients was a concern.

Researchers assessed data from 840 enrolled CLL patients, of whom 459 (55%) were previously untreated, and 381 (45%) had relapsed/refractory disease. In terms of therapy, chemoimmunotherapy was more common in previously untreated patients, compared with relapsed/refractory patients (42% vs. 23%), whereas ibrutinib was more frequently used in relapsed/refractory vs. previously untreated patients (51% vs. 39%), according to the researchers.

Fluorescent in situ hybridization (FISH) testing, TP53 mutation, and immunoglobulin heavy chain somatic hypermutation biomarker testing were performed infrequently across all patients at registry enrollment, according to the authors.

Among patients who were tested, the rate of mutated TP53 was the same for previously untreated (14/54; 26%) and relapsed/refractory patients (9/35; 26%). In those patients who were tested, 34% with del(17p), a chromosomal deletion, and 26% of mutated TP53 patients received chemoimmunotherapy combinations. The authors stated that this was concerning in that it contradicts consensus guidelines based on data from several clinical studies. Chemoimmunotherapy is not recommended for these high-risk patients because of poor disease and survival outcomes with this treatment strategy, according to the authors.

“Current clinical practice is not keeping pace with recommendations and guidelines for prognostic

marker testing and subsequent selection of appropriate therapy,” the authors stated.

“Even with the approval of novel agents and updated guidelines, low rates of prognostic biomarker testing may lead to suboptimal therapy choices for patients with unknown risk status. In addition, we note that the presence of high-risk features (del(17p) and TP53) is unfortunately not translating to choosing the optimal therapy for these patients,” the researchers concluded.

The study was sponsored by an AbbVie Company and Janssen. The authors reported consulting and grants from these and other pharmaceutical companies.

mlesney@mdedge.com

SOURCE: Mato AR et al. Clin Lymphoma Myeloma Leuk. 2020;20(3):174-83.

Recent advances in our understanding of asthma pathophysiology have led to the development of new treatment approaches to this chronic respiratory condition, which affects 25 million Americans or nearly 8% of the population.¹ As a result, asthma treatment options have expanded from just simple inhalers and corticosteroids to include biological therapies, immunotherapy, bronchial thermoplasty, and anti-inflammatory agents. This review will focus on the newer therapeutic options and provide guidance on when to seek expert pulmonary consultation (TABLE 1). But before we begin, it’s important to briefly review the pathophysiology of asthma and several key diagnostic considerations.

The pathophysiology of asthma provides key targets for therapy

There are 2 basic phenotypes of asthma—neutrophilic predominant and eosinophilic predominant—and 3 key components to its pathophysiology²:

Airway inflammation. Asthma is mediated through either a type 1 T-helper (Th-1) cell or a type 2 T-helper (Th-2) cell response, the pathways of which have a fair amount of overlap (FIGURE). In the neutrophilic-predominant phenotype, irritants, pollutants, and viruses trigger an innate Th-1 cell–mediated pathway that leads to subsequent neutrophil release. This asthma phenotype responds poorly to standard asthma therapy.^2-4

In the eosinophilic-predominant phenotype, environmental allergic antigens induce a Th-2 cell–mediated response in the airways of patients with asthma.^5-7 This creates a downstream effect on the release of interleukins (IL) including IL-4, IL-5, and IL-13. IL-4 triggers immunoglobulin (Ig) E release, which subsequently induces mast cells to release inflammatory cytokines, while IL-5 and IL-13 are responsible for eosinophilic response. These cytokines and eosinophils induce airway hyperresponsiveness, remodeling, and mucus production. Through repeated exposure, chronic inflammation develops and subsequently causes structural changes related to increased smooth muscle mass, goblet cell hyperplasia, and thickening of lamina reticularis.^8,9 Understanding of this pathobiological pathway has led to the development of anti-IgE and anti-IL-5 drugs (to be discussed shortly).

It is important to determine whether patients with asthma-COPD overlap syndrome are asthma predominant or COPD predominant, because appropriate first-line treatment will differ.

Airway obstruction. Early asthmatic response is due to acute bronchoconstriction secondary to IgE; this is followed by airway edema occurring 6 to 24 hours after an acute event (called late asthmatic response). The obstruction is worsened by an overproduction of mucus, which may take weeks to resolve.¹⁰ Longstanding inflammation can lead to structural changes and reduced airflow reversibility.

Bronchial hyperresponsiveness is induced by various forms of allergens, pollutants, or viral upper respiratory infections. Sympathetic control in the airway is mediated via beta-2 adrenoceptors expressed on airway smooth muscle, which are responsible for the effect of bronchodilation in response to albuterol.^11,12 Cholinergic pathways may further contribute to bronchial hyperresponsiveness and form the basis for the efficacy of anticholinergic therapy.^12,13

What we’ve learned about asthma can inform treatment decisions

Presentation may vary, as asthma has many forms including cough-variant asthma and exercise-induced asthma. Airflow limitation is typically identified through spirometry and characterized by reduced (< 70% in adults) forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) or bronchodilator response positivity (an increase in post-bronchodilator FEV₁ > 12% or FVC > 200 mL from baseline).² If spirometry is not diagnostic but suspicion for asthma remains, bronchial provocation testing or exercise challenge testing may be needed.

Continue to: Additional diagnostic considerations...

Additional diagnostic considerations may impact the treatment plan for patients with asthma:

Asthma and COPD. A history of smoking is a key factor in the diagnosis of chronic obstructive pulmonary disease (COPD)—but many patients with asthma are also smokers. This subgroup may have asthma-COPD overlap syndrome (ACOS). It is important to determine whether these patients are asthma predominant or COPD predominant, because appropriate first-line treatment will differ. Patients who are COPD predominant demonstrate reduced diffusion capacity (DLCO) and abnormal PaCO2 on arterial blood gas. They also may show more structural damage on chest computed tomography (CT) than patients with asthma do. Asthma-predominant patients are more likely to have eosinophilia.¹⁴

Patients with severe persistent asthma or frequent exacerbations, or those receiving step-up therapy, may require additional serologic testing. Specialized testing for IgE and eosinophil count, as well as a sensitized allergy panel, may help clinicians in selecting specific biological therapies for treatment of severe asthma (further discussion to follow). We recommend using a serum allergy panel, as it is a quick and easy way to identify patients with extrinsic allergies, whereas skin-based testing is often time consuming and may require referral to a specialist.^2,5,15

Aspergillus. An additional consideration is testing for Aspergillus antibodies. Aspergillus is a ubiquitous fungus found in the airways of humans. In patients with asthma, however, it can trigger an intense inflammatory response known as allergic bronchopulmonary aspergillosis. ABPA is not an infection. It should be considered in patients who have lived in a damp, old housing environment with possible mold exposure. Treatment of ABPA involves oral corticosteroids; there are varying reports of efficacy with voriconazole or itraconazole as suppressive therapy or steroid-sparing treatment.^16-18

Getting a handle on an ever-expanding asthma Tx arsenal

The goals of asthma treatment are symptom control and risk minimization. Treatment choices are dictated in part by disease severity (mild, moderate, severe) and classification (intermittent, persistent). Asthma therapy is traditionally described as step-up and step-down; TABLE 2 summarizes available pharmacotherapy for asthma and provides a framework for add-on therapy as the disease advances.

Continue to: Over the past decade...

Over the past decade, a number of therapeutic options have been introduced or added to the pantheon of asthma treatment.

Inhaled medications

This category includes inhaled corticosteroids (ICS), which are recommended for use alone or in combination with long-acting beta-agonists (LABA) or with long-acting muscarinic agonists (LAMA).

ICS is the first choice for long-term control of persistent asthma.² Its molecular effects include activating anti-inflammatory genes, switching off inflammatory genes, and inhibiting inflammatory cells, combined with enhancement of beta-2-adrenergic receptor expression. The cumulative effect is reduction in airway responsiveness in asthma patients.^19-22

LABAs are next in line in the step-up, step-down model of symptom management. LABAs should not be prescribed as stand-alone therapy in patients with asthma, as they have received a black box warning from the US Food and Drug Administration (FDA) for an increase in asthma-related death²³—a concern that has not been demonstrated with the combination of ICS-LABA.

LABAs should not be prescribed as stand-alone therapy in patients with asthma, as they have received an FDA black box warning.

LABAs cause smooth muscle relaxation in the lungs.²⁴ There are 3 combination products currently available: once-daily fluticasone furoate/vilanterol (Breo), twice-daily fluticasone propionate/salmeterol (Advair), and twice-daily budesonide/formoterol (Symbicort).

Continue to: Once-daily fluticasone furoate/vilanterol...

Once-daily fluticasone furoate/vilanterol has been shown to improve mean FEV₁.²⁵ In a 24-week, open-label, multicenter randomized controlled trial to evaluate the efficacy and safety of all 3 combination ICS-LABAs, preliminary results indicated that—at least in a tightly controlled setting—once-daily fluticasone furoate/vilanterol provides asthma control similar to the twice-daily combinations and is well tolerated.²⁶

Two ultra-long-acting (24-hour) LABAs, olodaterol (Striverdi Respimat) and indacaterol (Arcapta Neohaler), are being studied for possible use in asthma treatment. In a phase 2 trial investigating therapy for moderate-to-severe persistent asthma, 24-hour FEV₁ improved with olodeaterol when compared to placebo.²⁷

Another ongoing clinical trial is studying the effects of ultra-long-acting bronchodilator therapy (olodaterol vs combination olodaterol/tiotropium) in asthma patients who smoke and who are already using ICS (ClinicalTrials.gov NCT02682862). Indacaterol has been shown to be effective in the treatment of moderate-to-severe asthma in a once-a-day dosing regimen.²⁸ However, when compared to mometasone alone, a combination of indacaterol and mometasone demonstrated no statistically significant reduction in time to serious exacerbation.²⁹

The LAMA tiotropium is recommended as add-on therapy for patients whose asthma is uncontrolled despite use of low-dose ICS-LABA or as an alternative to high-dose ICS-LABA, per Global Initiative for Asthma (GINA) 2019 guidelines.¹⁵

Ideal candidates for biological therapy are patients who have exhausted other forms of severe asthma treatment.

Tiotropium induces bronchodilation by selectively inhibiting the action of acetylcholine at muscarinic (M) receptors in bronchial smooth muscles; it has a longer duration of action because of its slower dissociation from receptor types M₁ and M₃.³⁰ Tiotropium respimat (Spiriva, Tiova) has been approved for COPD for many years; in 2013, it was shown to prevent worsening of symptomatic asthma and increase time to first severe exacerbation.¹³ The FDA subsequently approved tiotropium as an add-on treatment for patients with uncontrolled asthma despite use of ICS-LABA.

Continue to: Glycopyrronium bromide...

Glycopyrronium bromide (glycopyrrolate, multiple brand names) and umeclidinium (Incruse Ellipta) are LAMAs that are approved for COPD treatment but have not yet been approved for patients who have asthma only.³¹

Biological therapies

In the past few years, improved understanding of asthma’s pathophysiology has led to the development of biological therapy for severe asthma. This therapy is directed at Th-2 inflammatory pathways (FIGURE) and targets various inflammatory markers, such as IgE, IL-5, and eosinophils.

Biologicals are not the first-line therapy for the management of severe asthma. Ideal candidates for this therapy are patients who have exhausted other forms of severe asthma treatment, including ICS-LABA, LAMA, leukotriene receptor antagonists, and mucus-clearing agents. Patients with frequent exacerbations who need continuous steroids or need steroids at least twice a year should be considered for biologicals.³²

All biological therapies must be administered in a clinical setting, as they carry risk for anaphylaxis. TABLE 3^15,33-47 summarizes all approved biologicals for the management of severe asthma.

Anti-IgE therapy. Omalizumab (Xolair) was the first approved biological therapy for severe asthma (in 2003). It is a recombinant humanized IgG1 monoclonal antibody that binds to free IgE and down regulates the inflammatory cascade. It is therefore best suited for patients with early-onset allergic asthma with a high IgE count. The dose and frequency (once or twice per month) of omalizumab are based on IgE levels and patient weight. Omalizumab reduces asthma exacerbation (up to 45%) and hospitalization (up to 85%).³⁴ Omalizumab also reduces the need for high-dose ICS-LABA therapy and improves quality of life (QoL).^33,34

Continue to: Its efficacy and safety...

Mepolizumab has shown a trend of greater benefit in patients with a very high eosinophil count.

Its efficacy and safety have been proven outside the clinical trial setting. Treatment response should be assessed over a 3- to 4-month period, using fractional exhalation of nitric oxide (FeNO); serial measurement of IgE levels is not recommended for this purpose. Once started, treatment should be considered long term, as discontinuation of treatment has been shown to lead to recurrence of symptoms and exacerbation.^35,36 Of note, the GINA guidelines recommend omalizumab over prednisone as add-on therapy for severe persistent asthma.¹⁵

Anti-IL-5 therapy. IL-5 is the main cytokine for growth, differentiation, and activation of eosinophils in the Th-2-mediated inflammatory cascade. Mepolizumab, reslizumab, and benralizumab are 3 FDA-approved anti-IL-5 monoclonal antibody therapies for severe eosinophilic asthma. Mepolizumab has been the most commonly studied anti-IL-5 therapy, while benralizumab, the latest of the 3, has a unique property of inducing eosinophilic apoptosis. There has been no direct comparison of the different anti-IL-5 therapies.

Mepolizumab (Nucala) is a mouse anti-human monoclonal antibody that binds to IL-5 and prevents it from binding to IL-5 receptors on the eosinophil surface. Mepolizumab should be considered in patients with a peripheral eosinophil count > 150 cells/mcL; it has shown a trend of greater benefit in patients with a very high eosinophil count (75% reduction in exacerbation with blood eosinophil count > 500 cells/mcL compared to 56% exacerbation reduction with blood eosinophil count > 150 cells/mcL).³⁷

Mepolizumab has consistently been shown to reduce asthma exacerbation (by about 50%) and emergency department (ED) visits and hospitalization (60%), when compared with placebo in clinical trials.^37,38 It also reduces the need for oral corticosteroids, an effect sustained for up to 52 weeks.^39,40 The Mepolizumab adjUnctive therapy in subjects with Severe eosinophiliC Asthma (MUSCA) study showed that mepolizumab was associated with significant improvement of health-related QoL, lung function, and asthma symptoms in patients with severe eosinophilic asthma.³⁸

GINA guidelines recommend mepolizumab as an add-on therapy for severe asthma. Mepolizumab is given as a fixed dose of 100 mg every 4 weeks. A 300-mg dose has also been approved for eosinophilic granulomatosis with polyangiitis. Monitoring with serial eosinophils might be of value in determining the efficacy of the drug. Mepolizumab is currently in clinical trials for a broad spectrum of diseases, including COPD, hyper-eosinophilic syndrome, and ABPA.

Continue to: Reslizumab (Cinqair)...

Reslizumab (Cinqair) is a rat anti-human monoclonal antibody of the IgG4κ subtype that binds to a small region of IL-5 and subsequently blocks IL-5 from binding to the IL-5 receptor complex on the cell surface of eosinophils. It is currently approved for use as a 3-mg/kg IV infusion every 4 weeks. In large clinical trials,^41-43 reslizumab decreased asthma exacerbation and improved QoL, asthma control, and lung function. Most of the study populations had an eosinophil count > 400 cells/mcL. A small study also suggested patients with severe eosinophilic asthma with prednisone dependency (10 mg/d) had better sputum eosinophilia suppression and asthma control with reslizumab when compared with mepolizumab.⁴⁴

Benralizumab (Fasenra) is a humanized IgG1 anti-IL-5 receptor α monoclonal antibody derived from mice. It induces apoptosis of eosinophils and, to a lesser extent, of basophils.⁴⁵ In clinical trials, it demonstrated a reduction in asthma exacerbation rate and improvement in prebronchodilator FEV₁ and asthma symptoms.^46,47 It does not need reconstitution, as the drug is dispensed as prefilled syringes with fixed non-weight-based dosing. Another potential advantage to benralizumab is that after the loading dose, subsequent doses are given every 8 weeks.

Bronchial thermoplasty

Bronchial thermoplasty (BT) is a novel nonpharmacologic intervention that entails the delivery of controlled radiofrequency-­generated heat via a catheter inserted into the bronchial tree of the lungs through a flexible bronchoscope. The potential mechanism of action is reduction in airway smooth muscle mass and inflammatory markers.

Evidence for BT started with the Asthma Intervention Research (AIR) and Research in Severe Asthma (RISA) trials.^48,49 In the AIR study, BT was shown to reduce the rate of mild exacerbations and improve morning peak expiratory flow and asthma scores at 12 months.⁴⁸ In the RISA trial, BT resulted in improvements in Asthma Quality of Life Questionnaire (AQLQ) score and need for rescue medication at 52 weeks, as well as a trend toward decrease in steroid use.⁴⁹

Bronchial thermoplasty results in clinically worthwhile reductions in severe exacerbations and ED visits in the year post treatment.

However, these studies were criticized for not having a placebo group—an issue addressed in the AIR2 trial, which compared bronchial thermoplasty with a sham procedure. AIR2 demonstrated improvements in AQLQ score and a 32% reduction in severe exacerbations and 84% fewer ED visits in the post-treatment period (up to 1 year post treatment).⁵⁰

Continue to: Both treatment groups...

Both treatment groups experienced an increase in respiratory adverse events: during the treatment period (up to 6 weeks post procedure), 16 subjects (8.4%) in the BT group required 19 hospitalizations for respiratory symptoms and 2 subjects (2%) in the sham group required 2 hospitalizations. A follow-up observational study involving a cohort of AIR2 patients demonstrated long-lasting effects of BT in asthma exacerbation frequency, ED visits, and stabilization of FEV₁ for up to 5 years.⁵¹

The Post-market Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma (PAS2) showed similar beneficial effects of BT on asthma control despite enrolling subjects who may have had poorer asthma control in the “real world” setting.⁵²

In summary, BT results in modest improvements in AQLQ scores and clinically worthwhile reductions in severe exacerbations and ED visits in the year post treatment, which may persist for up to 5 years. BT causes short-term increases in asthma-related morbidity, including hospital admissions. While there is encouraging data and the scope is increasing, BT remains limited to carefully selected (by a specialist) patients with severe asthma that is poorly controlled despite maximal inhaled therapy.

Immunotherapy

Immunotherapy for allergic disease is aimed at inducing immune tolerance to an allergen and alleviating allergic symptoms. This is done by administration of the allergen to which the patient is sensitive. There are 2 approaches: subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT; a dissolvable tablet under the tongue or an aqueous or liquid extract).

Immunotherapy is generally reserved for patients who have allergic symptoms with exposure to a trigger and evidence (through skin or serum testing) of specific IgE to that trigger, especially if there is poor response to pharmacotherapy and allergen avoidance. Overall, evidence in this field is limited: Most studies have included patients with mild asthma, and few studies have compared immunotherapy with pharmacologic therapy or used standardized outcomes, such as exacerbations.

Continue to: SCIT

SCIT. A 2010 Cochrane review concluded that SCIT reduces asthma symptoms and use of asthma medications and improves bronchial hyperreactivity. Adverse effects include uncommon anaphylactic reactions, which may be life-threatening.⁵³

SLIT has advantages over SCIT as it can be administered by patients or caregivers, does not require injections, and carries a much lower risk for anaphylaxis. Modest benefits have been seen in adults and children, but there is concern about the design of many early studies.

The potential benefits of allergen immunotherapy must be weighed against the risk for adverse effects, including anaphylaxis.

A 2015 Cochrane review of SLIT in asthma recommended further research using validated scales and important outcomes for patients and decision makers so that SLIT can be properly assessed as a clinical treatment for asthma.⁵⁴ A subsequently published study of SLIT for house dust mites (HDM) in patients with asthma and HDM allergic rhinitis demonstrated a modest reduction in use of ICS with high-dose SLIT.⁵⁵

In another recent study, among adults with HDM allergy-related asthma not well controlled by ICS, the addition of HDM SLIT to maintenance medications improved time to first moderate-or-severe asthma exacerbation during ICS reduction.⁵⁶ Additional studies are needed to assess long-term efficacy and safety. However, for patients who experience exacerbations despite use of a low-dose or medium-dose ICS-LABA combination, SLIT can now be considered as an add-on therapy.

Per the GINA guidelines, the potential benefits of allergen immunotherapy must be weighed against the risk for adverse effects, including anaphylaxis, and the inconvenience and cost of the prolonged course of therapy.¹⁵

Continue to: Azithromycin

Azithromycin

Macrolides have immunomodulatory and anti-inflammatory effects in addition to their antibacterial effects. Maintenance treatment with macrolides such as azithromycin has been proven to be effective in chronic neutrophilic airway diseases (FIGURE). There have been attempts to assess whether this therapy can be useful in asthma management, as well. Some randomized controlled trials and meta-analyses have shown conflicting results, and early studies were limited by lack of data, heterogeneous results, and inadequate study designs.

The AZithromycin Against pLacebo in Exacerbations of Asthma (AZALEA) study was a randomized, multicenter, double-blind, placebo-controlled clinical trial in the United Kingdom among patients requiring emergency care for acute asthma exacerbations. Azithromycin added to standard care for asthma attacks did not result in clinical benefit.⁵⁷ While azithromycin in acute exacerbation is not currently recommended, recent trials in outpatient settings have shown promise.

The AZIthromycin in Severe ASThma study (AZISAST) was a randomized, double-blind, placebo-controlled trial in subjects with exacerbation-prone severe asthma in Belgium. Low-dose azithromycin (250 mg 3 times a week) as an add-on treatment to combination ICS-LABA therapy for 6 months did not reduce the rate of severe asthma exacerbations or lower respiratory tract infection (LRTI). However, subjects with a non-eosinophilic variant (neutrophilic phenotype) experienced significant reduction in the rate of exacerbation and LRTI.⁵⁸

Chronic azithromycin might prove to be a useful agent in the long-term management of asthma patients whose disease is not well controlled on inhaled therapy

The recently published Asthma and Macrolides: the AZithromycin Efficacy and Safety Study (AMAZES) shows promise for chronic azithromycin therapy as an add-on to medium-to-high-dose inhaled steroids and a long-acting bronchodilator in adults with uncontrolled persistent asthma. This was a large multicenter, randomized, double-blind, placebo-controlled, parallel group trial in New Zealand and Australia. Patients were excluded if they had hearing impairment or abnormally prolonged QTc. Azithromycin at a dose of 500 mg 3 times a week for 48 months reduced asthma exacerbations and improved QoL compared to placebo. The effect was sustained between subgroups based on phenotypes (eosinophilic vs noneosinophilic; frequent exacerbators vs nonfrequent exacerbators) and even among those with symptom differences at baseline (eg, cough or sputum positivity). The rate of antibiotic courses for respiratory infectious episodes was significantly reduced in the azithromycin-treated group.⁵⁹

The take-away: Chronic azithromycin might prove to be a useful agent in the long-term management of asthma patients whose disease is not well controlled on inhaled therapy. Further studies on mechanism and effects of prolonged antibiotic use will shed more light. For more information, see When guideline treatment of asthma fails, consider a macrolide antibiotic; http://bit.ly/2vDAWc6.

Continue to: A new era

We have entered an exciting era of asthma management, with the introduction of several novel modalities, such as biological therapy and bronchial thermoplasty, as well as use of known drugs such as macrolides, immunotherapy, and LAMA. This was made possible through a better understanding of the biological pathways of asthma. Asthma management has moved toward more personalized, targeted therapy based on asthma phenotypes.

It’s important to remember, however, that pharmacological and nonpharmacological aspects of management—including inhaler techniques, adherence to inhaler therapy, vaccinations, control of asthma triggers, and smoking cessation—remain the foundation of optimal asthma management and need to be aggressively addressed before embarking on advanced treatment options. Patients whose asthma is not well controlled with inhaled medications or who have frequent exacerbations (requiring use of steroids) should be comanaged by an expert asthma specialist to explore all possible therapies.

CORRESPONDENCE
Mayur Rali, MD, 995 Newbridge Road, Bellmore, NY 11710; mrali@northwell.edu

Recent advances in our understanding of asthma pathophysiology have led to the development of new treatment approaches to this chronic respiratory condition, which affects 25 million Americans or nearly 8% of the population.¹ As a result, asthma treatment options have expanded from just simple inhalers and corticosteroids to include biological therapies, immunotherapy, bronchial thermoplasty, and anti-inflammatory agents. This review will focus on the newer therapeutic options and provide guidance on when to seek expert pulmonary consultation (TABLE 1). But before we begin, it’s important to briefly review the pathophysiology of asthma and several key diagnostic considerations.

The pathophysiology of asthma provides key targets for therapy

There are 2 basic phenotypes of asthma—neutrophilic predominant and eosinophilic predominant—and 3 key components to its pathophysiology²:

Airway inflammation. Asthma is mediated through either a type 1 T-helper (Th-1) cell or a type 2 T-helper (Th-2) cell response, the pathways of which have a fair amount of overlap (FIGURE). In the neutrophilic-predominant phenotype, irritants, pollutants, and viruses trigger an innate Th-1 cell–mediated pathway that leads to subsequent neutrophil release. This asthma phenotype responds poorly to standard asthma therapy.^2-4

In the eosinophilic-predominant phenotype, environmental allergic antigens induce a Th-2 cell–mediated response in the airways of patients with asthma.^5-7 This creates a downstream effect on the release of interleukins (IL) including IL-4, IL-5, and IL-13. IL-4 triggers immunoglobulin (Ig) E release, which subsequently induces mast cells to release inflammatory cytokines, while IL-5 and IL-13 are responsible for eosinophilic response. These cytokines and eosinophils induce airway hyperresponsiveness, remodeling, and mucus production. Through repeated exposure, chronic inflammation develops and subsequently causes structural changes related to increased smooth muscle mass, goblet cell hyperplasia, and thickening of lamina reticularis.^8,9 Understanding of this pathobiological pathway has led to the development of anti-IgE and anti-IL-5 drugs (to be discussed shortly).

It is important to determine whether patients with asthma-COPD overlap syndrome are asthma predominant or COPD predominant, because appropriate first-line treatment will differ.

Airway obstruction. Early asthmatic response is due to acute bronchoconstriction secondary to IgE; this is followed by airway edema occurring 6 to 24 hours after an acute event (called late asthmatic response). The obstruction is worsened by an overproduction of mucus, which may take weeks to resolve.¹⁰ Longstanding inflammation can lead to structural changes and reduced airflow reversibility.

Bronchial hyperresponsiveness is induced by various forms of allergens, pollutants, or viral upper respiratory infections. Sympathetic control in the airway is mediated via beta-2 adrenoceptors expressed on airway smooth muscle, which are responsible for the effect of bronchodilation in response to albuterol.^11,12 Cholinergic pathways may further contribute to bronchial hyperresponsiveness and form the basis for the efficacy of anticholinergic therapy.^12,13

What we’ve learned about asthma can inform treatment decisions

Presentation may vary, as asthma has many forms including cough-variant asthma and exercise-induced asthma. Airflow limitation is typically identified through spirometry and characterized by reduced (< 70% in adults) forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) or bronchodilator response positivity (an increase in post-bronchodilator FEV₁ > 12% or FVC > 200 mL from baseline).² If spirometry is not diagnostic but suspicion for asthma remains, bronchial provocation testing or exercise challenge testing may be needed.

Continue to: Additional diagnostic considerations...

Additional diagnostic considerations may impact the treatment plan for patients with asthma:

Asthma and COPD. A history of smoking is a key factor in the diagnosis of chronic obstructive pulmonary disease (COPD)—but many patients with asthma are also smokers. This subgroup may have asthma-COPD overlap syndrome (ACOS). It is important to determine whether these patients are asthma predominant or COPD predominant, because appropriate first-line treatment will differ. Patients who are COPD predominant demonstrate reduced diffusion capacity (DLCO) and abnormal PaCO2 on arterial blood gas. They also may show more structural damage on chest computed tomography (CT) than patients with asthma do. Asthma-predominant patients are more likely to have eosinophilia.¹⁴

Patients with severe persistent asthma or frequent exacerbations, or those receiving step-up therapy, may require additional serologic testing. Specialized testing for IgE and eosinophil count, as well as a sensitized allergy panel, may help clinicians in selecting specific biological therapies for treatment of severe asthma (further discussion to follow). We recommend using a serum allergy panel, as it is a quick and easy way to identify patients with extrinsic allergies, whereas skin-based testing is often time consuming and may require referral to a specialist.^2,5,15

Aspergillus. An additional consideration is testing for Aspergillus antibodies. Aspergillus is a ubiquitous fungus found in the airways of humans. In patients with asthma, however, it can trigger an intense inflammatory response known as allergic bronchopulmonary aspergillosis. ABPA is not an infection. It should be considered in patients who have lived in a damp, old housing environment with possible mold exposure. Treatment of ABPA involves oral corticosteroids; there are varying reports of efficacy with voriconazole or itraconazole as suppressive therapy or steroid-sparing treatment.^16-18

Getting a handle on an ever-expanding asthma Tx arsenal

The goals of asthma treatment are symptom control and risk minimization. Treatment choices are dictated in part by disease severity (mild, moderate, severe) and classification (intermittent, persistent). Asthma therapy is traditionally described as step-up and step-down; TABLE 2 summarizes available pharmacotherapy for asthma and provides a framework for add-on therapy as the disease advances.

Continue to: Over the past decade...

Over the past decade, a number of therapeutic options have been introduced or added to the pantheon of asthma treatment.

Inhaled medications

This category includes inhaled corticosteroids (ICS), which are recommended for use alone or in combination with long-acting beta-agonists (LABA) or with long-acting muscarinic agonists (LAMA).

ICS is the first choice for long-term control of persistent asthma.² Its molecular effects include activating anti-inflammatory genes, switching off inflammatory genes, and inhibiting inflammatory cells, combined with enhancement of beta-2-adrenergic receptor expression. The cumulative effect is reduction in airway responsiveness in asthma patients.^19-22

LABAs are next in line in the step-up, step-down model of symptom management. LABAs should not be prescribed as stand-alone therapy in patients with asthma, as they have received a black box warning from the US Food and Drug Administration (FDA) for an increase in asthma-related death²³—a concern that has not been demonstrated with the combination of ICS-LABA.

LABAs should not be prescribed as stand-alone therapy in patients with asthma, as they have received an FDA black box warning.

LABAs cause smooth muscle relaxation in the lungs.²⁴ There are 3 combination products currently available: once-daily fluticasone furoate/vilanterol (Breo), twice-daily fluticasone propionate/salmeterol (Advair), and twice-daily budesonide/formoterol (Symbicort).

Continue to: Once-daily fluticasone furoate/vilanterol...

Once-daily fluticasone furoate/vilanterol has been shown to improve mean FEV₁.²⁵ In a 24-week, open-label, multicenter randomized controlled trial to evaluate the efficacy and safety of all 3 combination ICS-LABAs, preliminary results indicated that—at least in a tightly controlled setting—once-daily fluticasone furoate/vilanterol provides asthma control similar to the twice-daily combinations and is well tolerated.²⁶

Two ultra-long-acting (24-hour) LABAs, olodaterol (Striverdi Respimat) and indacaterol (Arcapta Neohaler), are being studied for possible use in asthma treatment. In a phase 2 trial investigating therapy for moderate-to-severe persistent asthma, 24-hour FEV₁ improved with olodeaterol when compared to placebo.²⁷

Another ongoing clinical trial is studying the effects of ultra-long-acting bronchodilator therapy (olodaterol vs combination olodaterol/tiotropium) in asthma patients who smoke and who are already using ICS (ClinicalTrials.gov NCT02682862). Indacaterol has been shown to be effective in the treatment of moderate-to-severe asthma in a once-a-day dosing regimen.²⁸ However, when compared to mometasone alone, a combination of indacaterol and mometasone demonstrated no statistically significant reduction in time to serious exacerbation.²⁹

The LAMA tiotropium is recommended as add-on therapy for patients whose asthma is uncontrolled despite use of low-dose ICS-LABA or as an alternative to high-dose ICS-LABA, per Global Initiative for Asthma (GINA) 2019 guidelines.¹⁵

Ideal candidates for biological therapy are patients who have exhausted other forms of severe asthma treatment.

Tiotropium induces bronchodilation by selectively inhibiting the action of acetylcholine at muscarinic (M) receptors in bronchial smooth muscles; it has a longer duration of action because of its slower dissociation from receptor types M₁ and M₃.³⁰ Tiotropium respimat (Spiriva, Tiova) has been approved for COPD for many years; in 2013, it was shown to prevent worsening of symptomatic asthma and increase time to first severe exacerbation.¹³ The FDA subsequently approved tiotropium as an add-on treatment for patients with uncontrolled asthma despite use of ICS-LABA.

Continue to: Glycopyrronium bromide...

Glycopyrronium bromide (glycopyrrolate, multiple brand names) and umeclidinium (Incruse Ellipta) are LAMAs that are approved for COPD treatment but have not yet been approved for patients who have asthma only.³¹

Biological therapies

In the past few years, improved understanding of asthma’s pathophysiology has led to the development of biological therapy for severe asthma. This therapy is directed at Th-2 inflammatory pathways (FIGURE) and targets various inflammatory markers, such as IgE, IL-5, and eosinophils.

Biologicals are not the first-line therapy for the management of severe asthma. Ideal candidates for this therapy are patients who have exhausted other forms of severe asthma treatment, including ICS-LABA, LAMA, leukotriene receptor antagonists, and mucus-clearing agents. Patients with frequent exacerbations who need continuous steroids or need steroids at least twice a year should be considered for biologicals.³²

All biological therapies must be administered in a clinical setting, as they carry risk for anaphylaxis. TABLE 3^15,33-47 summarizes all approved biologicals for the management of severe asthma.

Anti-IgE therapy. Omalizumab (Xolair) was the first approved biological therapy for severe asthma (in 2003). It is a recombinant humanized IgG1 monoclonal antibody that binds to free IgE and down regulates the inflammatory cascade. It is therefore best suited for patients with early-onset allergic asthma with a high IgE count. The dose and frequency (once or twice per month) of omalizumab are based on IgE levels and patient weight. Omalizumab reduces asthma exacerbation (up to 45%) and hospitalization (up to 85%).³⁴ Omalizumab also reduces the need for high-dose ICS-LABA therapy and improves quality of life (QoL).^33,34

Continue to: Its efficacy and safety...

Mepolizumab has shown a trend of greater benefit in patients with a very high eosinophil count.

Its efficacy and safety have been proven outside the clinical trial setting. Treatment response should be assessed over a 3- to 4-month period, using fractional exhalation of nitric oxide (FeNO); serial measurement of IgE levels is not recommended for this purpose. Once started, treatment should be considered long term, as discontinuation of treatment has been shown to lead to recurrence of symptoms and exacerbation.^35,36 Of note, the GINA guidelines recommend omalizumab over prednisone as add-on therapy for severe persistent asthma.¹⁵

Anti-IL-5 therapy. IL-5 is the main cytokine for growth, differentiation, and activation of eosinophils in the Th-2-mediated inflammatory cascade. Mepolizumab, reslizumab, and benralizumab are 3 FDA-approved anti-IL-5 monoclonal antibody therapies for severe eosinophilic asthma. Mepolizumab has been the most commonly studied anti-IL-5 therapy, while benralizumab, the latest of the 3, has a unique property of inducing eosinophilic apoptosis. There has been no direct comparison of the different anti-IL-5 therapies.

Mepolizumab (Nucala) is a mouse anti-human monoclonal antibody that binds to IL-5 and prevents it from binding to IL-5 receptors on the eosinophil surface. Mepolizumab should be considered in patients with a peripheral eosinophil count > 150 cells/mcL; it has shown a trend of greater benefit in patients with a very high eosinophil count (75% reduction in exacerbation with blood eosinophil count > 500 cells/mcL compared to 56% exacerbation reduction with blood eosinophil count > 150 cells/mcL).³⁷

Mepolizumab has consistently been shown to reduce asthma exacerbation (by about 50%) and emergency department (ED) visits and hospitalization (60%), when compared with placebo in clinical trials.^37,38 It also reduces the need for oral corticosteroids, an effect sustained for up to 52 weeks.^39,40 The Mepolizumab adjUnctive therapy in subjects with Severe eosinophiliC Asthma (MUSCA) study showed that mepolizumab was associated with significant improvement of health-related QoL, lung function, and asthma symptoms in patients with severe eosinophilic asthma.³⁸

GINA guidelines recommend mepolizumab as an add-on therapy for severe asthma. Mepolizumab is given as a fixed dose of 100 mg every 4 weeks. A 300-mg dose has also been approved for eosinophilic granulomatosis with polyangiitis. Monitoring with serial eosinophils might be of value in determining the efficacy of the drug. Mepolizumab is currently in clinical trials for a broad spectrum of diseases, including COPD, hyper-eosinophilic syndrome, and ABPA.

Continue to: Reslizumab (Cinqair)...

Reslizumab (Cinqair) is a rat anti-human monoclonal antibody of the IgG4κ subtype that binds to a small region of IL-5 and subsequently blocks IL-5 from binding to the IL-5 receptor complex on the cell surface of eosinophils. It is currently approved for use as a 3-mg/kg IV infusion every 4 weeks. In large clinical trials,^41-43 reslizumab decreased asthma exacerbation and improved QoL, asthma control, and lung function. Most of the study populations had an eosinophil count > 400 cells/mcL. A small study also suggested patients with severe eosinophilic asthma with prednisone dependency (10 mg/d) had better sputum eosinophilia suppression and asthma control with reslizumab when compared with mepolizumab.⁴⁴

Benralizumab (Fasenra) is a humanized IgG1 anti-IL-5 receptor α monoclonal antibody derived from mice. It induces apoptosis of eosinophils and, to a lesser extent, of basophils.⁴⁵ In clinical trials, it demonstrated a reduction in asthma exacerbation rate and improvement in prebronchodilator FEV₁ and asthma symptoms.^46,47 It does not need reconstitution, as the drug is dispensed as prefilled syringes with fixed non-weight-based dosing. Another potential advantage to benralizumab is that after the loading dose, subsequent doses are given every 8 weeks.

Bronchial thermoplasty

Bronchial thermoplasty (BT) is a novel nonpharmacologic intervention that entails the delivery of controlled radiofrequency-­generated heat via a catheter inserted into the bronchial tree of the lungs through a flexible bronchoscope. The potential mechanism of action is reduction in airway smooth muscle mass and inflammatory markers.

Evidence for BT started with the Asthma Intervention Research (AIR) and Research in Severe Asthma (RISA) trials.^48,49 In the AIR study, BT was shown to reduce the rate of mild exacerbations and improve morning peak expiratory flow and asthma scores at 12 months.⁴⁸ In the RISA trial, BT resulted in improvements in Asthma Quality of Life Questionnaire (AQLQ) score and need for rescue medication at 52 weeks, as well as a trend toward decrease in steroid use.⁴⁹

Bronchial thermoplasty results in clinically worthwhile reductions in severe exacerbations and ED visits in the year post treatment.

However, these studies were criticized for not having a placebo group—an issue addressed in the AIR2 trial, which compared bronchial thermoplasty with a sham procedure. AIR2 demonstrated improvements in AQLQ score and a 32% reduction in severe exacerbations and 84% fewer ED visits in the post-treatment period (up to 1 year post treatment).⁵⁰

Continue to: Both treatment groups...

Both treatment groups experienced an increase in respiratory adverse events: during the treatment period (up to 6 weeks post procedure), 16 subjects (8.4%) in the BT group required 19 hospitalizations for respiratory symptoms and 2 subjects (2%) in the sham group required 2 hospitalizations. A follow-up observational study involving a cohort of AIR2 patients demonstrated long-lasting effects of BT in asthma exacerbation frequency, ED visits, and stabilization of FEV₁ for up to 5 years.⁵¹

The Post-market Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma (PAS2) showed similar beneficial effects of BT on asthma control despite enrolling subjects who may have had poorer asthma control in the “real world” setting.⁵²

In summary, BT results in modest improvements in AQLQ scores and clinically worthwhile reductions in severe exacerbations and ED visits in the year post treatment, which may persist for up to 5 years. BT causes short-term increases in asthma-related morbidity, including hospital admissions. While there is encouraging data and the scope is increasing, BT remains limited to carefully selected (by a specialist) patients with severe asthma that is poorly controlled despite maximal inhaled therapy.

Immunotherapy

Immunotherapy for allergic disease is aimed at inducing immune tolerance to an allergen and alleviating allergic symptoms. This is done by administration of the allergen to which the patient is sensitive. There are 2 approaches: subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT; a dissolvable tablet under the tongue or an aqueous or liquid extract).

Immunotherapy is generally reserved for patients who have allergic symptoms with exposure to a trigger and evidence (through skin or serum testing) of specific IgE to that trigger, especially if there is poor response to pharmacotherapy and allergen avoidance. Overall, evidence in this field is limited: Most studies have included patients with mild asthma, and few studies have compared immunotherapy with pharmacologic therapy or used standardized outcomes, such as exacerbations.

Continue to: SCIT

SCIT. A 2010 Cochrane review concluded that SCIT reduces asthma symptoms and use of asthma medications and improves bronchial hyperreactivity. Adverse effects include uncommon anaphylactic reactions, which may be life-threatening.⁵³

SLIT has advantages over SCIT as it can be administered by patients or caregivers, does not require injections, and carries a much lower risk for anaphylaxis. Modest benefits have been seen in adults and children, but there is concern about the design of many early studies.

The potential benefits of allergen immunotherapy must be weighed against the risk for adverse effects, including anaphylaxis.

A 2015 Cochrane review of SLIT in asthma recommended further research using validated scales and important outcomes for patients and decision makers so that SLIT can be properly assessed as a clinical treatment for asthma.⁵⁴ A subsequently published study of SLIT for house dust mites (HDM) in patients with asthma and HDM allergic rhinitis demonstrated a modest reduction in use of ICS with high-dose SLIT.⁵⁵

In another recent study, among adults with HDM allergy-related asthma not well controlled by ICS, the addition of HDM SLIT to maintenance medications improved time to first moderate-or-severe asthma exacerbation during ICS reduction.⁵⁶ Additional studies are needed to assess long-term efficacy and safety. However, for patients who experience exacerbations despite use of a low-dose or medium-dose ICS-LABA combination, SLIT can now be considered as an add-on therapy.

Per the GINA guidelines, the potential benefits of allergen immunotherapy must be weighed against the risk for adverse effects, including anaphylaxis, and the inconvenience and cost of the prolonged course of therapy.¹⁵

Continue to: Azithromycin

Azithromycin

Macrolides have immunomodulatory and anti-inflammatory effects in addition to their antibacterial effects. Maintenance treatment with macrolides such as azithromycin has been proven to be effective in chronic neutrophilic airway diseases (FIGURE). There have been attempts to assess whether this therapy can be useful in asthma management, as well. Some randomized controlled trials and meta-analyses have shown conflicting results, and early studies were limited by lack of data, heterogeneous results, and inadequate study designs.

The AZithromycin Against pLacebo in Exacerbations of Asthma (AZALEA) study was a randomized, multicenter, double-blind, placebo-controlled clinical trial in the United Kingdom among patients requiring emergency care for acute asthma exacerbations. Azithromycin added to standard care for asthma attacks did not result in clinical benefit.⁵⁷ While azithromycin in acute exacerbation is not currently recommended, recent trials in outpatient settings have shown promise.

The AZIthromycin in Severe ASThma study (AZISAST) was a randomized, double-blind, placebo-controlled trial in subjects with exacerbation-prone severe asthma in Belgium. Low-dose azithromycin (250 mg 3 times a week) as an add-on treatment to combination ICS-LABA therapy for 6 months did not reduce the rate of severe asthma exacerbations or lower respiratory tract infection (LRTI). However, subjects with a non-eosinophilic variant (neutrophilic phenotype) experienced significant reduction in the rate of exacerbation and LRTI.⁵⁸

Chronic azithromycin might prove to be a useful agent in the long-term management of asthma patients whose disease is not well controlled on inhaled therapy

The recently published Asthma and Macrolides: the AZithromycin Efficacy and Safety Study (AMAZES) shows promise for chronic azithromycin therapy as an add-on to medium-to-high-dose inhaled steroids and a long-acting bronchodilator in adults with uncontrolled persistent asthma. This was a large multicenter, randomized, double-blind, placebo-controlled, parallel group trial in New Zealand and Australia. Patients were excluded if they had hearing impairment or abnormally prolonged QTc. Azithromycin at a dose of 500 mg 3 times a week for 48 months reduced asthma exacerbations and improved QoL compared to placebo. The effect was sustained between subgroups based on phenotypes (eosinophilic vs noneosinophilic; frequent exacerbators vs nonfrequent exacerbators) and even among those with symptom differences at baseline (eg, cough or sputum positivity). The rate of antibiotic courses for respiratory infectious episodes was significantly reduced in the azithromycin-treated group.⁵⁹

The take-away: Chronic azithromycin might prove to be a useful agent in the long-term management of asthma patients whose disease is not well controlled on inhaled therapy. Further studies on mechanism and effects of prolonged antibiotic use will shed more light. For more information, see When guideline treatment of asthma fails, consider a macrolide antibiotic; http://bit.ly/2vDAWc6.

Continue to: A new era

We have entered an exciting era of asthma management, with the introduction of several novel modalities, such as biological therapy and bronchial thermoplasty, as well as use of known drugs such as macrolides, immunotherapy, and LAMA. This was made possible through a better understanding of the biological pathways of asthma. Asthma management has moved toward more personalized, targeted therapy based on asthma phenotypes.

It’s important to remember, however, that pharmacological and nonpharmacological aspects of management—including inhaler techniques, adherence to inhaler therapy, vaccinations, control of asthma triggers, and smoking cessation—remain the foundation of optimal asthma management and need to be aggressively addressed before embarking on advanced treatment options. Patients whose asthma is not well controlled with inhaled medications or who have frequent exacerbations (requiring use of steroids) should be comanaged by an expert asthma specialist to explore all possible therapies.

CORRESPONDENCE
Mayur Rali, MD, 995 Newbridge Road, Bellmore, NY 11710; mrali@northwell.edu

Recent advances in our understanding of asthma pathophysiology have led to the development of new treatment approaches to this chronic respiratory condition, which affects 25 million Americans or nearly 8% of the population.¹ As a result, asthma treatment options have expanded from just simple inhalers and corticosteroids to include biological therapies, immunotherapy, bronchial thermoplasty, and anti-inflammatory agents. This review will focus on the newer therapeutic options and provide guidance on when to seek expert pulmonary consultation (TABLE 1). But before we begin, it’s important to briefly review the pathophysiology of asthma and several key diagnostic considerations.

The pathophysiology of asthma provides key targets for therapy

There are 2 basic phenotypes of asthma—neutrophilic predominant and eosinophilic predominant—and 3 key components to its pathophysiology²:

Airway inflammation. Asthma is mediated through either a type 1 T-helper (Th-1) cell or a type 2 T-helper (Th-2) cell response, the pathways of which have a fair amount of overlap (FIGURE). In the neutrophilic-predominant phenotype, irritants, pollutants, and viruses trigger an innate Th-1 cell–mediated pathway that leads to subsequent neutrophil release. This asthma phenotype responds poorly to standard asthma therapy.^2-4

In the eosinophilic-predominant phenotype, environmental allergic antigens induce a Th-2 cell–mediated response in the airways of patients with asthma.^5-7 This creates a downstream effect on the release of interleukins (IL) including IL-4, IL-5, and IL-13. IL-4 triggers immunoglobulin (Ig) E release, which subsequently induces mast cells to release inflammatory cytokines, while IL-5 and IL-13 are responsible for eosinophilic response. These cytokines and eosinophils induce airway hyperresponsiveness, remodeling, and mucus production. Through repeated exposure, chronic inflammation develops and subsequently causes structural changes related to increased smooth muscle mass, goblet cell hyperplasia, and thickening of lamina reticularis.^8,9 Understanding of this pathobiological pathway has led to the development of anti-IgE and anti-IL-5 drugs (to be discussed shortly).

It is important to determine whether patients with asthma-COPD overlap syndrome are asthma predominant or COPD predominant, because appropriate first-line treatment will differ.

Airway obstruction. Early asthmatic response is due to acute bronchoconstriction secondary to IgE; this is followed by airway edema occurring 6 to 24 hours after an acute event (called late asthmatic response). The obstruction is worsened by an overproduction of mucus, which may take weeks to resolve.¹⁰ Longstanding inflammation can lead to structural changes and reduced airflow reversibility.

Bronchial hyperresponsiveness is induced by various forms of allergens, pollutants, or viral upper respiratory infections. Sympathetic control in the airway is mediated via beta-2 adrenoceptors expressed on airway smooth muscle, which are responsible for the effect of bronchodilation in response to albuterol.^11,12 Cholinergic pathways may further contribute to bronchial hyperresponsiveness and form the basis for the efficacy of anticholinergic therapy.^12,13

What we’ve learned about asthma can inform treatment decisions

Presentation may vary, as asthma has many forms including cough-variant asthma and exercise-induced asthma. Airflow limitation is typically identified through spirometry and characterized by reduced (< 70% in adults) forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) or bronchodilator response positivity (an increase in post-bronchodilator FEV₁ > 12% or FVC > 200 mL from baseline).² If spirometry is not diagnostic but suspicion for asthma remains, bronchial provocation testing or exercise challenge testing may be needed.

Continue to: Additional diagnostic considerations...

Additional diagnostic considerations may impact the treatment plan for patients with asthma:

Asthma and COPD. A history of smoking is a key factor in the diagnosis of chronic obstructive pulmonary disease (COPD)—but many patients with asthma are also smokers. This subgroup may have asthma-COPD overlap syndrome (ACOS). It is important to determine whether these patients are asthma predominant or COPD predominant, because appropriate first-line treatment will differ. Patients who are COPD predominant demonstrate reduced diffusion capacity (DLCO) and abnormal PaCO2 on arterial blood gas. They also may show more structural damage on chest computed tomography (CT) than patients with asthma do. Asthma-predominant patients are more likely to have eosinophilia.¹⁴

Patients with severe persistent asthma or frequent exacerbations, or those receiving step-up therapy, may require additional serologic testing. Specialized testing for IgE and eosinophil count, as well as a sensitized allergy panel, may help clinicians in selecting specific biological therapies for treatment of severe asthma (further discussion to follow). We recommend using a serum allergy panel, as it is a quick and easy way to identify patients with extrinsic allergies, whereas skin-based testing is often time consuming and may require referral to a specialist.^2,5,15

Aspergillus. An additional consideration is testing for Aspergillus antibodies. Aspergillus is a ubiquitous fungus found in the airways of humans. In patients with asthma, however, it can trigger an intense inflammatory response known as allergic bronchopulmonary aspergillosis. ABPA is not an infection. It should be considered in patients who have lived in a damp, old housing environment with possible mold exposure. Treatment of ABPA involves oral corticosteroids; there are varying reports of efficacy with voriconazole or itraconazole as suppressive therapy or steroid-sparing treatment.^16-18

Getting a handle on an ever-expanding asthma Tx arsenal

The goals of asthma treatment are symptom control and risk minimization. Treatment choices are dictated in part by disease severity (mild, moderate, severe) and classification (intermittent, persistent). Asthma therapy is traditionally described as step-up and step-down; TABLE 2 summarizes available pharmacotherapy for asthma and provides a framework for add-on therapy as the disease advances.

Continue to: Over the past decade...

Over the past decade, a number of therapeutic options have been introduced or added to the pantheon of asthma treatment.

Inhaled medications

This category includes inhaled corticosteroids (ICS), which are recommended for use alone or in combination with long-acting beta-agonists (LABA) or with long-acting muscarinic agonists (LAMA).

ICS is the first choice for long-term control of persistent asthma.² Its molecular effects include activating anti-inflammatory genes, switching off inflammatory genes, and inhibiting inflammatory cells, combined with enhancement of beta-2-adrenergic receptor expression. The cumulative effect is reduction in airway responsiveness in asthma patients.^19-22

LABAs are next in line in the step-up, step-down model of symptom management. LABAs should not be prescribed as stand-alone therapy in patients with asthma, as they have received a black box warning from the US Food and Drug Administration (FDA) for an increase in asthma-related death²³—a concern that has not been demonstrated with the combination of ICS-LABA.

LABAs should not be prescribed as stand-alone therapy in patients with asthma, as they have received an FDA black box warning.

LABAs cause smooth muscle relaxation in the lungs.²⁴ There are 3 combination products currently available: once-daily fluticasone furoate/vilanterol (Breo), twice-daily fluticasone propionate/salmeterol (Advair), and twice-daily budesonide/formoterol (Symbicort).

Continue to: Once-daily fluticasone furoate/vilanterol...

Once-daily fluticasone furoate/vilanterol has been shown to improve mean FEV₁.²⁵ In a 24-week, open-label, multicenter randomized controlled trial to evaluate the efficacy and safety of all 3 combination ICS-LABAs, preliminary results indicated that—at least in a tightly controlled setting—once-daily fluticasone furoate/vilanterol provides asthma control similar to the twice-daily combinations and is well tolerated.²⁶

Two ultra-long-acting (24-hour) LABAs, olodaterol (Striverdi Respimat) and indacaterol (Arcapta Neohaler), are being studied for possible use in asthma treatment. In a phase 2 trial investigating therapy for moderate-to-severe persistent asthma, 24-hour FEV₁ improved with olodeaterol when compared to placebo.²⁷

Another ongoing clinical trial is studying the effects of ultra-long-acting bronchodilator therapy (olodaterol vs combination olodaterol/tiotropium) in asthma patients who smoke and who are already using ICS (ClinicalTrials.gov NCT02682862). Indacaterol has been shown to be effective in the treatment of moderate-to-severe asthma in a once-a-day dosing regimen.²⁸ However, when compared to mometasone alone, a combination of indacaterol and mometasone demonstrated no statistically significant reduction in time to serious exacerbation.²⁹

The LAMA tiotropium is recommended as add-on therapy for patients whose asthma is uncontrolled despite use of low-dose ICS-LABA or as an alternative to high-dose ICS-LABA, per Global Initiative for Asthma (GINA) 2019 guidelines.¹⁵

Ideal candidates for biological therapy are patients who have exhausted other forms of severe asthma treatment.

Tiotropium induces bronchodilation by selectively inhibiting the action of acetylcholine at muscarinic (M) receptors in bronchial smooth muscles; it has a longer duration of action because of its slower dissociation from receptor types M₁ and M₃.³⁰ Tiotropium respimat (Spiriva, Tiova) has been approved for COPD for many years; in 2013, it was shown to prevent worsening of symptomatic asthma and increase time to first severe exacerbation.¹³ The FDA subsequently approved tiotropium as an add-on treatment for patients with uncontrolled asthma despite use of ICS-LABA.

Continue to: Glycopyrronium bromide...

Glycopyrronium bromide (glycopyrrolate, multiple brand names) and umeclidinium (Incruse Ellipta) are LAMAs that are approved for COPD treatment but have not yet been approved for patients who have asthma only.³¹

Biological therapies

In the past few years, improved understanding of asthma’s pathophysiology has led to the development of biological therapy for severe asthma. This therapy is directed at Th-2 inflammatory pathways (FIGURE) and targets various inflammatory markers, such as IgE, IL-5, and eosinophils.

Biologicals are not the first-line therapy for the management of severe asthma. Ideal candidates for this therapy are patients who have exhausted other forms of severe asthma treatment, including ICS-LABA, LAMA, leukotriene receptor antagonists, and mucus-clearing agents. Patients with frequent exacerbations who need continuous steroids or need steroids at least twice a year should be considered for biologicals.³²

All biological therapies must be administered in a clinical setting, as they carry risk for anaphylaxis. TABLE 3^15,33-47 summarizes all approved biologicals for the management of severe asthma.

Anti-IgE therapy. Omalizumab (Xolair) was the first approved biological therapy for severe asthma (in 2003). It is a recombinant humanized IgG1 monoclonal antibody that binds to free IgE and down regulates the inflammatory cascade. It is therefore best suited for patients with early-onset allergic asthma with a high IgE count. The dose and frequency (once or twice per month) of omalizumab are based on IgE levels and patient weight. Omalizumab reduces asthma exacerbation (up to 45%) and hospitalization (up to 85%).³⁴ Omalizumab also reduces the need for high-dose ICS-LABA therapy and improves quality of life (QoL).^33,34

Continue to: Its efficacy and safety...

Mepolizumab has shown a trend of greater benefit in patients with a very high eosinophil count.

Its efficacy and safety have been proven outside the clinical trial setting. Treatment response should be assessed over a 3- to 4-month period, using fractional exhalation of nitric oxide (FeNO); serial measurement of IgE levels is not recommended for this purpose. Once started, treatment should be considered long term, as discontinuation of treatment has been shown to lead to recurrence of symptoms and exacerbation.^35,36 Of note, the GINA guidelines recommend omalizumab over prednisone as add-on therapy for severe persistent asthma.¹⁵

Anti-IL-5 therapy. IL-5 is the main cytokine for growth, differentiation, and activation of eosinophils in the Th-2-mediated inflammatory cascade. Mepolizumab, reslizumab, and benralizumab are 3 FDA-approved anti-IL-5 monoclonal antibody therapies for severe eosinophilic asthma. Mepolizumab has been the most commonly studied anti-IL-5 therapy, while benralizumab, the latest of the 3, has a unique property of inducing eosinophilic apoptosis. There has been no direct comparison of the different anti-IL-5 therapies.

Mepolizumab (Nucala) is a mouse anti-human monoclonal antibody that binds to IL-5 and prevents it from binding to IL-5 receptors on the eosinophil surface. Mepolizumab should be considered in patients with a peripheral eosinophil count > 150 cells/mcL; it has shown a trend of greater benefit in patients with a very high eosinophil count (75% reduction in exacerbation with blood eosinophil count > 500 cells/mcL compared to 56% exacerbation reduction with blood eosinophil count > 150 cells/mcL).³⁷

Mepolizumab has consistently been shown to reduce asthma exacerbation (by about 50%) and emergency department (ED) visits and hospitalization (60%), when compared with placebo in clinical trials.^37,38 It also reduces the need for oral corticosteroids, an effect sustained for up to 52 weeks.^39,40 The Mepolizumab adjUnctive therapy in subjects with Severe eosinophiliC Asthma (MUSCA) study showed that mepolizumab was associated with significant improvement of health-related QoL, lung function, and asthma symptoms in patients with severe eosinophilic asthma.³⁸

GINA guidelines recommend mepolizumab as an add-on therapy for severe asthma. Mepolizumab is given as a fixed dose of 100 mg every 4 weeks. A 300-mg dose has also been approved for eosinophilic granulomatosis with polyangiitis. Monitoring with serial eosinophils might be of value in determining the efficacy of the drug. Mepolizumab is currently in clinical trials for a broad spectrum of diseases, including COPD, hyper-eosinophilic syndrome, and ABPA.

Continue to: Reslizumab (Cinqair)...

Reslizumab (Cinqair) is a rat anti-human monoclonal antibody of the IgG4κ subtype that binds to a small region of IL-5 and subsequently blocks IL-5 from binding to the IL-5 receptor complex on the cell surface of eosinophils. It is currently approved for use as a 3-mg/kg IV infusion every 4 weeks. In large clinical trials,^41-43 reslizumab decreased asthma exacerbation and improved QoL, asthma control, and lung function. Most of the study populations had an eosinophil count > 400 cells/mcL. A small study also suggested patients with severe eosinophilic asthma with prednisone dependency (10 mg/d) had better sputum eosinophilia suppression and asthma control with reslizumab when compared with mepolizumab.⁴⁴

Benralizumab (Fasenra) is a humanized IgG1 anti-IL-5 receptor α monoclonal antibody derived from mice. It induces apoptosis of eosinophils and, to a lesser extent, of basophils.⁴⁵ In clinical trials, it demonstrated a reduction in asthma exacerbation rate and improvement in prebronchodilator FEV₁ and asthma symptoms.^46,47 It does not need reconstitution, as the drug is dispensed as prefilled syringes with fixed non-weight-based dosing. Another potential advantage to benralizumab is that after the loading dose, subsequent doses are given every 8 weeks.

Bronchial thermoplasty

Bronchial thermoplasty (BT) is a novel nonpharmacologic intervention that entails the delivery of controlled radiofrequency-­generated heat via a catheter inserted into the bronchial tree of the lungs through a flexible bronchoscope. The potential mechanism of action is reduction in airway smooth muscle mass and inflammatory markers.

Evidence for BT started with the Asthma Intervention Research (AIR) and Research in Severe Asthma (RISA) trials.^48,49 In the AIR study, BT was shown to reduce the rate of mild exacerbations and improve morning peak expiratory flow and asthma scores at 12 months.⁴⁸ In the RISA trial, BT resulted in improvements in Asthma Quality of Life Questionnaire (AQLQ) score and need for rescue medication at 52 weeks, as well as a trend toward decrease in steroid use.⁴⁹

Bronchial thermoplasty results in clinically worthwhile reductions in severe exacerbations and ED visits in the year post treatment.

However, these studies were criticized for not having a placebo group—an issue addressed in the AIR2 trial, which compared bronchial thermoplasty with a sham procedure. AIR2 demonstrated improvements in AQLQ score and a 32% reduction in severe exacerbations and 84% fewer ED visits in the post-treatment period (up to 1 year post treatment).⁵⁰

Continue to: Both treatment groups...

Both treatment groups experienced an increase in respiratory adverse events: during the treatment period (up to 6 weeks post procedure), 16 subjects (8.4%) in the BT group required 19 hospitalizations for respiratory symptoms and 2 subjects (2%) in the sham group required 2 hospitalizations. A follow-up observational study involving a cohort of AIR2 patients demonstrated long-lasting effects of BT in asthma exacerbation frequency, ED visits, and stabilization of FEV₁ for up to 5 years.⁵¹

The Post-market Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma (PAS2) showed similar beneficial effects of BT on asthma control despite enrolling subjects who may have had poorer asthma control in the “real world” setting.⁵²

In summary, BT results in modest improvements in AQLQ scores and clinically worthwhile reductions in severe exacerbations and ED visits in the year post treatment, which may persist for up to 5 years. BT causes short-term increases in asthma-related morbidity, including hospital admissions. While there is encouraging data and the scope is increasing, BT remains limited to carefully selected (by a specialist) patients with severe asthma that is poorly controlled despite maximal inhaled therapy.

Immunotherapy

Immunotherapy for allergic disease is aimed at inducing immune tolerance to an allergen and alleviating allergic symptoms. This is done by administration of the allergen to which the patient is sensitive. There are 2 approaches: subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT; a dissolvable tablet under the tongue or an aqueous or liquid extract).

Immunotherapy is generally reserved for patients who have allergic symptoms with exposure to a trigger and evidence (through skin or serum testing) of specific IgE to that trigger, especially if there is poor response to pharmacotherapy and allergen avoidance. Overall, evidence in this field is limited: Most studies have included patients with mild asthma, and few studies have compared immunotherapy with pharmacologic therapy or used standardized outcomes, such as exacerbations.

Continue to: SCIT

SCIT. A 2010 Cochrane review concluded that SCIT reduces asthma symptoms and use of asthma medications and improves bronchial hyperreactivity. Adverse effects include uncommon anaphylactic reactions, which may be life-threatening.⁵³

SLIT has advantages over SCIT as it can be administered by patients or caregivers, does not require injections, and carries a much lower risk for anaphylaxis. Modest benefits have been seen in adults and children, but there is concern about the design of many early studies.

The potential benefits of allergen immunotherapy must be weighed against the risk for adverse effects, including anaphylaxis.

A 2015 Cochrane review of SLIT in asthma recommended further research using validated scales and important outcomes for patients and decision makers so that SLIT can be properly assessed as a clinical treatment for asthma.⁵⁴ A subsequently published study of SLIT for house dust mites (HDM) in patients with asthma and HDM allergic rhinitis demonstrated a modest reduction in use of ICS with high-dose SLIT.⁵⁵

In another recent study, among adults with HDM allergy-related asthma not well controlled by ICS, the addition of HDM SLIT to maintenance medications improved time to first moderate-or-severe asthma exacerbation during ICS reduction.⁵⁶ Additional studies are needed to assess long-term efficacy and safety. However, for patients who experience exacerbations despite use of a low-dose or medium-dose ICS-LABA combination, SLIT can now be considered as an add-on therapy.

Per the GINA guidelines, the potential benefits of allergen immunotherapy must be weighed against the risk for adverse effects, including anaphylaxis, and the inconvenience and cost of the prolonged course of therapy.¹⁵

Continue to: Azithromycin

Azithromycin

Macrolides have immunomodulatory and anti-inflammatory effects in addition to their antibacterial effects. Maintenance treatment with macrolides such as azithromycin has been proven to be effective in chronic neutrophilic airway diseases (FIGURE). There have been attempts to assess whether this therapy can be useful in asthma management, as well. Some randomized controlled trials and meta-analyses have shown conflicting results, and early studies were limited by lack of data, heterogeneous results, and inadequate study designs.

The AZithromycin Against pLacebo in Exacerbations of Asthma (AZALEA) study was a randomized, multicenter, double-blind, placebo-controlled clinical trial in the United Kingdom among patients requiring emergency care for acute asthma exacerbations. Azithromycin added to standard care for asthma attacks did not result in clinical benefit.⁵⁷ While azithromycin in acute exacerbation is not currently recommended, recent trials in outpatient settings have shown promise.

The AZIthromycin in Severe ASThma study (AZISAST) was a randomized, double-blind, placebo-controlled trial in subjects with exacerbation-prone severe asthma in Belgium. Low-dose azithromycin (250 mg 3 times a week) as an add-on treatment to combination ICS-LABA therapy for 6 months did not reduce the rate of severe asthma exacerbations or lower respiratory tract infection (LRTI). However, subjects with a non-eosinophilic variant (neutrophilic phenotype) experienced significant reduction in the rate of exacerbation and LRTI.⁵⁸

Chronic azithromycin might prove to be a useful agent in the long-term management of asthma patients whose disease is not well controlled on inhaled therapy

The recently published Asthma and Macrolides: the AZithromycin Efficacy and Safety Study (AMAZES) shows promise for chronic azithromycin therapy as an add-on to medium-to-high-dose inhaled steroids and a long-acting bronchodilator in adults with uncontrolled persistent asthma. This was a large multicenter, randomized, double-blind, placebo-controlled, parallel group trial in New Zealand and Australia. Patients were excluded if they had hearing impairment or abnormally prolonged QTc. Azithromycin at a dose of 500 mg 3 times a week for 48 months reduced asthma exacerbations and improved QoL compared to placebo. The effect was sustained between subgroups based on phenotypes (eosinophilic vs noneosinophilic; frequent exacerbators vs nonfrequent exacerbators) and even among those with symptom differences at baseline (eg, cough or sputum positivity). The rate of antibiotic courses for respiratory infectious episodes was significantly reduced in the azithromycin-treated group.⁵⁹

The take-away: Chronic azithromycin might prove to be a useful agent in the long-term management of asthma patients whose disease is not well controlled on inhaled therapy. Further studies on mechanism and effects of prolonged antibiotic use will shed more light. For more information, see When guideline treatment of asthma fails, consider a macrolide antibiotic; http://bit.ly/2vDAWc6.

Continue to: A new era

We have entered an exciting era of asthma management, with the introduction of several novel modalities, such as biological therapy and bronchial thermoplasty, as well as use of known drugs such as macrolides, immunotherapy, and LAMA. This was made possible through a better understanding of the biological pathways of asthma. Asthma management has moved toward more personalized, targeted therapy based on asthma phenotypes.

It’s important to remember, however, that pharmacological and nonpharmacological aspects of management—including inhaler techniques, adherence to inhaler therapy, vaccinations, control of asthma triggers, and smoking cessation—remain the foundation of optimal asthma management and need to be aggressively addressed before embarking on advanced treatment options. Patients whose asthma is not well controlled with inhaled medications or who have frequent exacerbations (requiring use of steroids) should be comanaged by an expert asthma specialist to explore all possible therapies.

CORRESPONDENCE
Mayur Rali, MD, 995 Newbridge Road, Bellmore, NY 11710; mrali@northwell.edu

Cervical pannus is a disease that could easily develop in an active-duty soldier or veteran. The disease has been associated with trauma and rheumatoid arthritis, or can be idiopathic. For years, cervical pannus has been closely tied to rheumatoid arthritis; however, a study published in 2019 showed that only 28% of patients with cervical pannus had an associated diagnosis of rheumatoid arthritis.¹ In the same study, 18% of patients had undergone some type of prior cervical spine surgery as the next most common cause. The condition also can occur years after an injury.

Background

In the US, 42,000 veterans are living with spinal cord disease, and thousands of these veterans have surgery every year.² Service men and women and veterans are at risk for cervical pannus as they age especially if they have a history of rheumatoid arthritis, cervical spine surgery, trauma, and numerous other causes. It is critical for health care providers who treat this population to understand cervical pannus, how to recognize it, and how to identify patients at risk. A cervical pannus can be life threatening if not detected and treated properly.

There is no clear definition for cervical pannus. Some researchers think of it as the chronically inflamed synovial membrane in patients with rheumatoid arthritis (RA); others consider it as a specialized synovial membrane derived from vascular soft tissue structures at or near the bone synovial membrane.³ The pathogenesis for developing a pannus is not well understood, and little is known when a pannus begins or its initial location. A pannus formation can occur in any synovial joint in the body, such as wrists, metacarpophalangeal joint, proximal interphalangeal joint, and cervical joints.

A cervical pannus can cause serious complications. It can lead to a cervical subluxation in up to 4% of patients with RA, or it also can occur spontaneously in some patients without RA especially those with trauma or cancer.⁴

There are 2 suggested mechanisms by which the synovial membrane proliferates. It was originally believed that T cells from the chronic inflamed joint lead to the pannus formation by initiating an autoimmune reaction through the production of different cytokines against arthritogenic agents.^3-5 These cytokines increase inflammation by recruiting neutrophils and activating various kinds of macrophages that might lead to increased osteoclast activity.⁶ Osteoclastic activity can damage bone and allow the synovium to penetrate the bone, forming the pannus.

Another proposed mechanism is that the synovial cells hyperpolarize and hypertrophy automatically without T-cell help by expressing oncogenes and their proteins.³ In either case, angiogenesis follows this proliferation and increases the influx of inflammatory cells into the joints, which can lead to more destruction.⁷ This increase in blood supply to the synovial membrane is important in the growth of the pannus and can have a damaging effect to cartilage, bone, and joints.^4,7

Cervical pannus can progress in patients with prolonged use of corticosteroids.⁸ Because a pannus can put pressure on any segment of the cervical spine and the cranio-cervical junction leading to cervical instability, patients with this condition may present with a variety of clinical symptoms.⁹ The most frequently reported clinical features include neck pain, easy fatigability, difficulty walking, abnormal gait, increased clumsiness, and numbness and tingling in the arms. Patients also may complain of neck stiffness and decreased neck motion.¹⁰Cervical pannus is most frequently seen in patients with RA. However, patients without a RA diagnosis and incidental atlantoaxial pannus on cervical spine magnetic resonance imaging (MRI) are unlikely to have previously undiagnosed RA.¹¹

Case Presentation

A 70-year-old white woman presented to the neurology clinic at Gretna Medical Center in Virginia in December 2016 with constant headache and imbalance that started in September 2016. She characterized the pain as predominately pressure (6 on a 10-point pain scale) with occasional shooting pains. The pain started at the left occipital lobe and radiated toward the left temporal lobe and left eye. The patient also stated that it was very difficult to lay her head down on a pillow to sleep and that she had to use a recliner in order to sleep over the past 3 months. She reported that the headache felt slightly worse if she had a lot of repetitive head and neck movements during the day. There was no photophobia, phonophobia, nausea, vomiting, facial paresthesias, lacrimation, nasal congestion, confusion, or impaired speech.

The patient’s lack of balance, which resulted in an unsteady gait, had started 1 month before and had increased significantly in the past 2 to 3 weeks. She stated that the unsteady gait was associated with numbness in her right upper and lower extremities, although more intense in the right lower extremity. Aside from the headaches, paresthesia, and unsteady gait, the patient reported no other major symptoms. She did not smoke tobacco or drink alcohol. Her family history revealed that her brothers had heart disease.

The patient’s vital signs at physical examination included heart rate, 83 beats per minute; blood pressure, 159/75 mm hg; temporal temperature, 97.9 °F; and respiratory rate, 20 breaths per minute. The patient’s gait was unsteady, needing stabilization by holding on to her husband’s arm, slightly favoring right lower extremity. Finger-to-nose test, rapid alternating movements, heel-knee-shin testing were all normal. The Romberg sign was positive. The patient could rise on toes and heels with slight balance disturbance. Deep tendon reflexes and reflexes in the upper and lower extremities was symmetric 2+ bilaterally. Musculoskeletal examination revealed strength and tone in all major muscle groups and demonstrated symmetrical movements with no fasciculation noted. A rheumatologic evaluation showed no abnormalities, including inspection of hands, feet, major joints, and other range of motion, besides her neck. The rest of the physical, cognitive, and neurologic examination findings were otherwise unremarkable. A routine rheumatologic laboratory evaluation was negative.

A head computed tomography ordered before coming to the clinic showed normal results. An MRI of the head was obtained to evaluate for ischemic cause or structural abnormality (Figures 1 and 2). Given the patient’s presentation and the pattern seen on the MRI results, it was determined that large pannus posterior to the dens, severely narrowing the spinal canal, was most likely the diagnosis. A second opinion confirmed the diagnosis, and a second MRI revealed stabilization with no signs of enhancement.

The patient was advised to meet with a neurosurgeon to remove the pannus. The patient agreed on occiput to C2 posterior instrument arthrodesis as well as decompression. A plain film radiograph showed C2-occipital repair after surgery (Figure 3). The patient recovered in the neurosurgical intensive care unit, and the rest of the recovery was uncomplicated. She showed some improvement in her headaches and unsteady gait. A postoperative pathologic evaluation of tissue was not available. She was referred to a rheumatologist to rule out an autoimmune disease as the cause for this pannus, but no autoimmune disease was found.

Discussion

Cervical pannus is relatively uncommon in those without RA. However, there are multiple reasons that a patient could develop a cervical pannus. Cervical pannus in RA and cervical pannus without RA may mimic each other clinically, but medical management is distinctly different. Consequently, a rheumatology consult is necessary to ensure that there is no undiagnosed autoimmune disorder. Our patient did not have RA, and a neurosurgery intervention was needed to manage her headaches and unsteady gait. Although we could not isolate a cause of this patient’s cervical pannus development, we believed that nonintervention would adversely affect this patient.

The course of pannus progression can be fatal especially if left untreated.¹² MRI can detect a pannus and may be helpful for planning surgery.¹³ Surgical resection has been the treatment of choice for patients with neurologic symptoms.¹⁴ However, some cases have reported resolution of pannus associated with RA and other forms of chronic atlantoaxial instability only after posterior stabilization.¹⁴In order to manage pannus, cervical spine examination for the diagnosis of cervical involvement is encouraged to prevent morbidity and mortality.¹³ There are new data that demonstrated the potential of using retinoid X receptor agonists, such as bexarotene, as a treatment against the development and progression of pannus.¹⁴

Conclusions

We present a patient with cervical pannus disease without RA whose diagnosis was based on the pathognomonic pattern seen on MRI. She showed a clinically significant recovery with an occiput to C2 posterior instrument arthrodesis as well as decompression. She showed marked improvements in her headaches and unsteady gait. This case report highlights the importance of realizing cervical pannus as a disease found in patients without RA. It serves as an alert to clinicians for timely detection, diagnosis, and initiation of treatment to prevent mortality and long-term neurologic sequelae of cervical pannus.

Although further studies of early diagnosis and treatment for cervical pannus are warranted, we propose that including pannus in a differential diagnosis for patients with no RA could be lifesaving.

Cervical pannus is a disease that could easily develop in an active-duty soldier or veteran. The disease has been associated with trauma and rheumatoid arthritis, or can be idiopathic. For years, cervical pannus has been closely tied to rheumatoid arthritis; however, a study published in 2019 showed that only 28% of patients with cervical pannus had an associated diagnosis of rheumatoid arthritis.¹ In the same study, 18% of patients had undergone some type of prior cervical spine surgery as the next most common cause. The condition also can occur years after an injury.

Background

In the US, 42,000 veterans are living with spinal cord disease, and thousands of these veterans have surgery every year.² Service men and women and veterans are at risk for cervical pannus as they age especially if they have a history of rheumatoid arthritis, cervical spine surgery, trauma, and numerous other causes. It is critical for health care providers who treat this population to understand cervical pannus, how to recognize it, and how to identify patients at risk. A cervical pannus can be life threatening if not detected and treated properly.

There is no clear definition for cervical pannus. Some researchers think of it as the chronically inflamed synovial membrane in patients with rheumatoid arthritis (RA); others consider it as a specialized synovial membrane derived from vascular soft tissue structures at or near the bone synovial membrane.³ The pathogenesis for developing a pannus is not well understood, and little is known when a pannus begins or its initial location. A pannus formation can occur in any synovial joint in the body, such as wrists, metacarpophalangeal joint, proximal interphalangeal joint, and cervical joints.

A cervical pannus can cause serious complications. It can lead to a cervical subluxation in up to 4% of patients with RA, or it also can occur spontaneously in some patients without RA especially those with trauma or cancer.⁴

There are 2 suggested mechanisms by which the synovial membrane proliferates. It was originally believed that T cells from the chronic inflamed joint lead to the pannus formation by initiating an autoimmune reaction through the production of different cytokines against arthritogenic agents.^3-5 These cytokines increase inflammation by recruiting neutrophils and activating various kinds of macrophages that might lead to increased osteoclast activity.⁶ Osteoclastic activity can damage bone and allow the synovium to penetrate the bone, forming the pannus.

Another proposed mechanism is that the synovial cells hyperpolarize and hypertrophy automatically without T-cell help by expressing oncogenes and their proteins.³ In either case, angiogenesis follows this proliferation and increases the influx of inflammatory cells into the joints, which can lead to more destruction.⁷ This increase in blood supply to the synovial membrane is important in the growth of the pannus and can have a damaging effect to cartilage, bone, and joints.^4,7

Cervical pannus can progress in patients with prolonged use of corticosteroids.⁸ Because a pannus can put pressure on any segment of the cervical spine and the cranio-cervical junction leading to cervical instability, patients with this condition may present with a variety of clinical symptoms.⁹ The most frequently reported clinical features include neck pain, easy fatigability, difficulty walking, abnormal gait, increased clumsiness, and numbness and tingling in the arms. Patients also may complain of neck stiffness and decreased neck motion.¹⁰Cervical pannus is most frequently seen in patients with RA. However, patients without a RA diagnosis and incidental atlantoaxial pannus on cervical spine magnetic resonance imaging (MRI) are unlikely to have previously undiagnosed RA.¹¹

Case Presentation

A 70-year-old white woman presented to the neurology clinic at Gretna Medical Center in Virginia in December 2016 with constant headache and imbalance that started in September 2016. She characterized the pain as predominately pressure (6 on a 10-point pain scale) with occasional shooting pains. The pain started at the left occipital lobe and radiated toward the left temporal lobe and left eye. The patient also stated that it was very difficult to lay her head down on a pillow to sleep and that she had to use a recliner in order to sleep over the past 3 months. She reported that the headache felt slightly worse if she had a lot of repetitive head and neck movements during the day. There was no photophobia, phonophobia, nausea, vomiting, facial paresthesias, lacrimation, nasal congestion, confusion, or impaired speech.

The patient’s lack of balance, which resulted in an unsteady gait, had started 1 month before and had increased significantly in the past 2 to 3 weeks. She stated that the unsteady gait was associated with numbness in her right upper and lower extremities, although more intense in the right lower extremity. Aside from the headaches, paresthesia, and unsteady gait, the patient reported no other major symptoms. She did not smoke tobacco or drink alcohol. Her family history revealed that her brothers had heart disease.

The patient’s vital signs at physical examination included heart rate, 83 beats per minute; blood pressure, 159/75 mm hg; temporal temperature, 97.9 °F; and respiratory rate, 20 breaths per minute. The patient’s gait was unsteady, needing stabilization by holding on to her husband’s arm, slightly favoring right lower extremity. Finger-to-nose test, rapid alternating movements, heel-knee-shin testing were all normal. The Romberg sign was positive. The patient could rise on toes and heels with slight balance disturbance. Deep tendon reflexes and reflexes in the upper and lower extremities was symmetric 2+ bilaterally. Musculoskeletal examination revealed strength and tone in all major muscle groups and demonstrated symmetrical movements with no fasciculation noted. A rheumatologic evaluation showed no abnormalities, including inspection of hands, feet, major joints, and other range of motion, besides her neck. The rest of the physical, cognitive, and neurologic examination findings were otherwise unremarkable. A routine rheumatologic laboratory evaluation was negative.

A head computed tomography ordered before coming to the clinic showed normal results. An MRI of the head was obtained to evaluate for ischemic cause or structural abnormality (Figures 1 and 2). Given the patient’s presentation and the pattern seen on the MRI results, it was determined that large pannus posterior to the dens, severely narrowing the spinal canal, was most likely the diagnosis. A second opinion confirmed the diagnosis, and a second MRI revealed stabilization with no signs of enhancement.

The patient was advised to meet with a neurosurgeon to remove the pannus. The patient agreed on occiput to C2 posterior instrument arthrodesis as well as decompression. A plain film radiograph showed C2-occipital repair after surgery (Figure 3). The patient recovered in the neurosurgical intensive care unit, and the rest of the recovery was uncomplicated. She showed some improvement in her headaches and unsteady gait. A postoperative pathologic evaluation of tissue was not available. She was referred to a rheumatologist to rule out an autoimmune disease as the cause for this pannus, but no autoimmune disease was found.

Discussion

Cervical pannus is relatively uncommon in those without RA. However, there are multiple reasons that a patient could develop a cervical pannus. Cervical pannus in RA and cervical pannus without RA may mimic each other clinically, but medical management is distinctly different. Consequently, a rheumatology consult is necessary to ensure that there is no undiagnosed autoimmune disorder. Our patient did not have RA, and a neurosurgery intervention was needed to manage her headaches and unsteady gait. Although we could not isolate a cause of this patient’s cervical pannus development, we believed that nonintervention would adversely affect this patient.

The course of pannus progression can be fatal especially if left untreated.¹² MRI can detect a pannus and may be helpful for planning surgery.¹³ Surgical resection has been the treatment of choice for patients with neurologic symptoms.¹⁴ However, some cases have reported resolution of pannus associated with RA and other forms of chronic atlantoaxial instability only after posterior stabilization.¹⁴In order to manage pannus, cervical spine examination for the diagnosis of cervical involvement is encouraged to prevent morbidity and mortality.¹³ There are new data that demonstrated the potential of using retinoid X receptor agonists, such as bexarotene, as a treatment against the development and progression of pannus.¹⁴

Conclusions

We present a patient with cervical pannus disease without RA whose diagnosis was based on the pathognomonic pattern seen on MRI. She showed a clinically significant recovery with an occiput to C2 posterior instrument arthrodesis as well as decompression. She showed marked improvements in her headaches and unsteady gait. This case report highlights the importance of realizing cervical pannus as a disease found in patients without RA. It serves as an alert to clinicians for timely detection, diagnosis, and initiation of treatment to prevent mortality and long-term neurologic sequelae of cervical pannus.

Although further studies of early diagnosis and treatment for cervical pannus are warranted, we propose that including pannus in a differential diagnosis for patients with no RA could be lifesaving.

Cervical pannus is a disease that could easily develop in an active-duty soldier or veteran. The disease has been associated with trauma and rheumatoid arthritis, or can be idiopathic. For years, cervical pannus has been closely tied to rheumatoid arthritis; however, a study published in 2019 showed that only 28% of patients with cervical pannus had an associated diagnosis of rheumatoid arthritis.¹ In the same study, 18% of patients had undergone some type of prior cervical spine surgery as the next most common cause. The condition also can occur years after an injury.

Background

In the US, 42,000 veterans are living with spinal cord disease, and thousands of these veterans have surgery every year.² Service men and women and veterans are at risk for cervical pannus as they age especially if they have a history of rheumatoid arthritis, cervical spine surgery, trauma, and numerous other causes. It is critical for health care providers who treat this population to understand cervical pannus, how to recognize it, and how to identify patients at risk. A cervical pannus can be life threatening if not detected and treated properly.

There is no clear definition for cervical pannus. Some researchers think of it as the chronically inflamed synovial membrane in patients with rheumatoid arthritis (RA); others consider it as a specialized synovial membrane derived from vascular soft tissue structures at or near the bone synovial membrane.³ The pathogenesis for developing a pannus is not well understood, and little is known when a pannus begins or its initial location. A pannus formation can occur in any synovial joint in the body, such as wrists, metacarpophalangeal joint, proximal interphalangeal joint, and cervical joints.

A cervical pannus can cause serious complications. It can lead to a cervical subluxation in up to 4% of patients with RA, or it also can occur spontaneously in some patients without RA especially those with trauma or cancer.⁴

There are 2 suggested mechanisms by which the synovial membrane proliferates. It was originally believed that T cells from the chronic inflamed joint lead to the pannus formation by initiating an autoimmune reaction through the production of different cytokines against arthritogenic agents.^3-5 These cytokines increase inflammation by recruiting neutrophils and activating various kinds of macrophages that might lead to increased osteoclast activity.⁶ Osteoclastic activity can damage bone and allow the synovium to penetrate the bone, forming the pannus.

Another proposed mechanism is that the synovial cells hyperpolarize and hypertrophy automatically without T-cell help by expressing oncogenes and their proteins.³ In either case, angiogenesis follows this proliferation and increases the influx of inflammatory cells into the joints, which can lead to more destruction.⁷ This increase in blood supply to the synovial membrane is important in the growth of the pannus and can have a damaging effect to cartilage, bone, and joints.^4,7

Cervical pannus can progress in patients with prolonged use of corticosteroids.⁸ Because a pannus can put pressure on any segment of the cervical spine and the cranio-cervical junction leading to cervical instability, patients with this condition may present with a variety of clinical symptoms.⁹ The most frequently reported clinical features include neck pain, easy fatigability, difficulty walking, abnormal gait, increased clumsiness, and numbness and tingling in the arms. Patients also may complain of neck stiffness and decreased neck motion.¹⁰Cervical pannus is most frequently seen in patients with RA. However, patients without a RA diagnosis and incidental atlantoaxial pannus on cervical spine magnetic resonance imaging (MRI) are unlikely to have previously undiagnosed RA.¹¹

Case Presentation

A 70-year-old white woman presented to the neurology clinic at Gretna Medical Center in Virginia in December 2016 with constant headache and imbalance that started in September 2016. She characterized the pain as predominately pressure (6 on a 10-point pain scale) with occasional shooting pains. The pain started at the left occipital lobe and radiated toward the left temporal lobe and left eye. The patient also stated that it was very difficult to lay her head down on a pillow to sleep and that she had to use a recliner in order to sleep over the past 3 months. She reported that the headache felt slightly worse if she had a lot of repetitive head and neck movements during the day. There was no photophobia, phonophobia, nausea, vomiting, facial paresthesias, lacrimation, nasal congestion, confusion, or impaired speech.

The patient’s lack of balance, which resulted in an unsteady gait, had started 1 month before and had increased significantly in the past 2 to 3 weeks. She stated that the unsteady gait was associated with numbness in her right upper and lower extremities, although more intense in the right lower extremity. Aside from the headaches, paresthesia, and unsteady gait, the patient reported no other major symptoms. She did not smoke tobacco or drink alcohol. Her family history revealed that her brothers had heart disease.

The patient’s vital signs at physical examination included heart rate, 83 beats per minute; blood pressure, 159/75 mm hg; temporal temperature, 97.9 °F; and respiratory rate, 20 breaths per minute. The patient’s gait was unsteady, needing stabilization by holding on to her husband’s arm, slightly favoring right lower extremity. Finger-to-nose test, rapid alternating movements, heel-knee-shin testing were all normal. The Romberg sign was positive. The patient could rise on toes and heels with slight balance disturbance. Deep tendon reflexes and reflexes in the upper and lower extremities was symmetric 2+ bilaterally. Musculoskeletal examination revealed strength and tone in all major muscle groups and demonstrated symmetrical movements with no fasciculation noted. A rheumatologic evaluation showed no abnormalities, including inspection of hands, feet, major joints, and other range of motion, besides her neck. The rest of the physical, cognitive, and neurologic examination findings were otherwise unremarkable. A routine rheumatologic laboratory evaluation was negative.

A head computed tomography ordered before coming to the clinic showed normal results. An MRI of the head was obtained to evaluate for ischemic cause or structural abnormality (Figures 1 and 2). Given the patient’s presentation and the pattern seen on the MRI results, it was determined that large pannus posterior to the dens, severely narrowing the spinal canal, was most likely the diagnosis. A second opinion confirmed the diagnosis, and a second MRI revealed stabilization with no signs of enhancement.

The patient was advised to meet with a neurosurgeon to remove the pannus. The patient agreed on occiput to C2 posterior instrument arthrodesis as well as decompression. A plain film radiograph showed C2-occipital repair after surgery (Figure 3). The patient recovered in the neurosurgical intensive care unit, and the rest of the recovery was uncomplicated. She showed some improvement in her headaches and unsteady gait. A postoperative pathologic evaluation of tissue was not available. She was referred to a rheumatologist to rule out an autoimmune disease as the cause for this pannus, but no autoimmune disease was found.

Discussion

Cervical pannus is relatively uncommon in those without RA. However, there are multiple reasons that a patient could develop a cervical pannus. Cervical pannus in RA and cervical pannus without RA may mimic each other clinically, but medical management is distinctly different. Consequently, a rheumatology consult is necessary to ensure that there is no undiagnosed autoimmune disorder. Our patient did not have RA, and a neurosurgery intervention was needed to manage her headaches and unsteady gait. Although we could not isolate a cause of this patient’s cervical pannus development, we believed that nonintervention would adversely affect this patient.

The course of pannus progression can be fatal especially if left untreated.¹² MRI can detect a pannus and may be helpful for planning surgery.¹³ Surgical resection has been the treatment of choice for patients with neurologic symptoms.¹⁴ However, some cases have reported resolution of pannus associated with RA and other forms of chronic atlantoaxial instability only after posterior stabilization.¹⁴In order to manage pannus, cervical spine examination for the diagnosis of cervical involvement is encouraged to prevent morbidity and mortality.¹³ There are new data that demonstrated the potential of using retinoid X receptor agonists, such as bexarotene, as a treatment against the development and progression of pannus.¹⁴

Conclusions

We present a patient with cervical pannus disease without RA whose diagnosis was based on the pathognomonic pattern seen on MRI. She showed a clinically significant recovery with an occiput to C2 posterior instrument arthrodesis as well as decompression. She showed marked improvements in her headaches and unsteady gait. This case report highlights the importance of realizing cervical pannus as a disease found in patients without RA. It serves as an alert to clinicians for timely detection, diagnosis, and initiation of treatment to prevent mortality and long-term neurologic sequelae of cervical pannus.

Although further studies of early diagnosis and treatment for cervical pannus are warranted, we propose that including pannus in a differential diagnosis for patients with no RA could be lifesaving.